Methods of treating subject with cdc42-specific inhibitor

Abstract

To provide methods for prolonging or regulating aspects of a subject's life or immunizing the subject, in particular, methods for prolonging or regulating longevity, survival time, life span, and health span in the subject's life.SOLUTION: A method comprises administering to a subject in need of treatment an effective amount of at least one Cdc42-specific inhibitor, wherein the Cdc42-specific inhibitor exemplified by the following formula is administered to the subject before or after the subject receives one or more immunization dosages.SELECTED DRAWING: Figure 1d

Description

[Technical Field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made possible through funding from the National Institutes of Health, awarded HL076604 and DK07776 This invention was made with U.S. government support under the 2002 Act. The U.S. government has certain rights in this invention. do.

[0002] Administration of at least one inhibitor of a GTPase, such as Cdc42 GTPase, Aspects of a subject's lifespan, such as increasing lifespan, survival time, lifespan, and healthspan Methods are provided for extending the activity of a small number of GTPases, such as Cdc42 GTPase. Also provided are methods of immunizing a subject by administering at least one inhibitor and one or more immunizations. will be done. [Background technology]

[0003] Rho family GTPases regulate cytoskeletal rearrangements, gene expression, cell cycle progression, Molecular signals that control signaling pathways that regulate cell survival and other cellular processes It is an itchy (Etienne-Manneville, 2002).

[0004] Rho family proteins are members of three major branches of the Ras superfamily. The development of inhibitors of Rho family GTPases is a promising therapeutic approach. This could be a promising new avenue for compounding. Summary of the Invention

[0005] The embodiments disclosed herein provide a method for extending an aspect of a subject's lifespan, or In some embodiments, the present invention relates to a method for immunizing an elephant in need of treatment. and administering to an elephant an effective amount of at least one Cdc42-specific inhibitor. Methods are provided for increasing survival, life span, and health span. In some embodiments, a subject in need of immunization is administered an effective amount of at least one Cdc42 administering a specific inhibitor and administering one or more immunization doses to said subject. In some embodiments, the method comprises administering to a subject a serogroup comprising: From prolonging life, prolonging survival, prolonging lifespan, prolonging healthspan, or immunization In some embodiments, the subject further comprises identifying the subject as one who would benefit. is the subject's age, the subject's current medical condition, the subject's current treatment, the subject's Cdc42 activity, and and / or are identified based on the methylation status of the CpG sites of interest.

[0006] In some embodiments, the Cdc42-specific inhibitor is a small molecule. In one embodiment, the small molecule is a Cdc42 activity-specific inhibitor (CASIN). In the above embodiment, the chemical structure of CASIN is: [ka]

[0007] In some embodiments, the small molecule may be a single enantiomer, a mixture of enantiomers, or both. a compound of formula (I) as a compound, a pharmaceutically acceptable salt, a solvate, or a polymorph thereof; Including, [ka] During the ceremony, Y is selected from the group consisting of -OR7, -NR8R9, and -NNR8R9; R7 is C 1~6Alkyl, -(CH2) u C 3~7 Cycloalkyl, C 2~6 Arke Nill, C 1~6 Alkoxy, Hydroxy-C 1~6 Alkyl, phenyl, up to 5 full C substituted with Oro 1~6 Alkyl and C substituted with up to 5 fluoro 1~6 a alkoxy, 1~6 Alkyl, -(CH2) u C 3~7 Shik Roalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C 1~6 Alkyl , phenyl are each optionally halo, -CN, -OH, C 1~6 Alkoxy, hetero Aryl, R 19 , and -OR 20 one or more independently selected from the group consisting of is substituted with the above substituents, R8 and R9 are each independently hydrogen or R 20 or R8 and R9, optionally together with the nitrogen to which they are attached, can be indolinyl, pyrrolidinyl, , piperidinyl, piperazinyl, or morpholinyl, each of which is selected from the group consisting of halo, cyano, No, Nitro, Hydroxy, C 1~6 Alkyl, (CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C 1~6 Alkyl, phenyl, Large 5 fluoro-substituted C 1~6 Alkyl and up to 5 fluoro substituted TaC 1~6and optionally one or more substituents each independently selected from the group consisting of alkoxy. or R8 and R2 are joined together to form a ring; 1~ 3 alkyl, Each R 20 is C 1~6 Alkyl, C 3~7 the group consisting of cycloalkyl, and phenyl wherein C is independently selected from 1~6 Alkyl, C 3~7 Cycloalkyl, and phenyl are each independently R 21 and R 22 one or more substituents selected from the group consisting of optionally replaced by Each R 21 are independently selected from the group consisting of halo, cyano, nitro, and hydroxy. R, Each R 22 separately, C 1~6 Alkyl, C 1~6 Alkoxy-(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, Hydroxy C 1~6 Alkyl, R 19 and -O R 20 and each of which is selected from the group consisting of halo, cyano, nitro, hydroxy, C1 ~6 Alkyl, and C 1~6 1 independently selected from the group consisting of alkoxy optionally substituted with one or more substituents, each u is independently 0, 1, 2, 3, or 4; R2 is hydrogen or C 1~6 Alkyl, C 3~7 Cycloalkyl, and phenoxy wherein C is selected from the group consisting of: 1~6 Alkyl, C 3~7 cycloalkyl, and Phenyl is independently selected from halo, cyano, nitro, hydroxy, and C 1~6 Alkyl, -(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, hydroxy Droxy-C 1~6 C substituted with alkyl, phenyl, and up to 5 fluoro 1~6 Al Kill, C substituted with up to 5 fluoro 1~6 Alkoxy and, each independently, halo Ro, cyano, nitro, hydroxy, C 1~6 Alkyl, and C 1~6 From alkoxy -O(CH2) optionally substituted with one or more substituents selected from the group u From phenyl or R8 and R2 are optionally substituted with one or more substituents selected from the group consisting of Alkyl C that joins together as a ring 1~3 And R3, R4, R5 and R6 are each independently hydrogen, halo, cyano, nitro, hydroxyl Roxi, C 1~6 Alkyl, (CH2) u C 3~7 Cycloalkyl, -O(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C 1~ C substituted with 6 alkyl, phenyl, and up to 5 fluoro 1~6 Alkyl, and max. Five fluoro-substituted C 1~6 alkoxy, wherein C 1~6 Alkyl, (CH2) u C 3~7 Cycloalkyl, -O(CH2) u C3~7 Cycloal Kill, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C 1~6 Alkyl and and phenyl each optionally have one or more R 23 is replaced by Each R 23 are independently halo, cyano, nitro, hydroxy, C 1~6 Alkyl, -(C H2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, hydroxy C-C 1~6 C substituted with alkyl, phenyl, and up to 5 fluoro 1~6 Alkyl, and C substituted with up to five fluoro 1~6 alkoxy, The phenyl group can be substituted with halo, cyano, nitro, hydroxy, C 1~6 Alkyl, -(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C1 ~6 Alkyl, C substituted with up to 5 fluoro 1~6 Alkyl, and up to 5 fluorines Substituted C 1~6 one or more substituents independently selected from the group consisting of alkoxy optionally substituted with substituents, Each R 19 are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups. C replaced by 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy is an aryl group, Each R20 are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups. C replaced by 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy is hydrogen or aryl, When Y is NR8R9, R8 and R2 may optionally be joined together to form a ring. Bonding alkyl C 1~3 However, However, R8 and R2 are linked together to form a ring. 1~3 became provided that, in this case, R4 is not substituted with hydroxyl.

[0008] Also provided herein are methods of immunizing a subject, the methods comprising administering a Cdc42-specific inhibitor to a subject. The immunizing agent is administered to the subject before the subject receives one or more immunization doses. In some embodiments, the Cdc42-specific inhibitor is administered to the subject after the subject has received one or more immunization doses. In some embodiments, a Cdc42-specific inhibitor is administered to the subject. is administered to the subject both before and after receiving one or more immunization doses. In an embodiment, the Cdc42-specific inhibitor is administered to the subject once or more than once. In some embodiments, the subject receives one or more treatments for the same or different diseases. In some embodiments, the subject's immune system is compromised. In some embodiments, Cdc42 activity in a subject is determined by Cdc42-specific inhibition. This is determined prior to administering the agent to said subject.

[0009] administering to a subject in need of treatment an effective amount of at least one Cdc42-specific inhibitor Methods for increasing lifespan, survival time, life span, and health span, including: Also presented herein are methods for predicting longevity, lifespan, and / or healthspan survival time. The expected increases are approximately 1% to 100%, approximately 1% to 90%, approximately 1% to 80%, and approximately 1% to 70%. , about 1% to 60%, about 1% to 50%, about 1% to 40%, about 1% to 30%, about 1% to 20% , about 5% to 15%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, approximately 13%, approximately 14%, approximately 15%, or a range bounded by any of the preceding figures The percentages are used to calculate the expected lifespan, survival time, lifespan, or health of a subject. In some embodiments, the expected life span, survival time, or lifespan of a subject is The span, or health span, is the median or mean expected value of similarly situated subjects. In some embodiments, the expected increase is statistically significant. [Brief explanation of the drawings]

[0010] [Figure 1](a) Scheme showing the experimental setup for an in vivo model to determine the effects of a Cdc42-specific inhibitor (e.g., CASIN) on mammalian lifespan. (b) Mass spectrometry quantification of Cdc42-specific inhibitor (e.g., CASIN) concentrations in the serum of 75-week-old C57BL / 6 mice injected with an IP dose of 25 mg / kg CASIN every 24 h for four consecutive days. Blood was collected 3, 24, and 48 h after the final injection on day 4. n = 26 at 3 h, 12 at 24 h, and 7 at 48 h. (c) Representative images and quantification of Western blot / pulldown of total and active Cdc42 (Cdc42GTP) in bone marrow cells from young (10-week-old, labeled "Control Young") and aged (75-week-old, labeled "Control Old") control and CASIN-treated (labeled "CASIN Old") C57BL / 6 mice. n = 4 mice per group. *p < 0.05 vs. old controls by one-way ANOVA and Tukey's multiple comparison test. (d) Old control (labeled "old control" and represented by the black line bifurcating at approximately 75 weeks and terminating on the x-axis between 120 and 135 weeks) and CASIN (labeled "old CASIN" and represented by the gray line bifurcating at approximately 75 weeks and terminating on the x-axis between 150 and 165 weeks) treated mice. Treatments were performed according to the carton scheme shown in panel a. n = 18 for controls and 17 for CASIN. p < 0.0004 by Mantel-Cox test and p < 0.0032 by Gehan-Breslow-Wilcoxon test. Median survival time for controls was 123.5 weeks and for CASIN 136 weeks. (e)-(h) Cytokine array results. According to the scheme in panel a, serum was collected from the same mice on day 0 (old control) and day 7 (old control and old CASIN, indicated on the graph with the additional descriptor "d7"). Seven young (10-week-old) C57BL / 6 female mice were bled along with the old mice on day 0, and the serum was used as the young control sample for the cytokine array. The number of experimental mice included was n = 7 for young control (labeled "young control"), 27 for old control day 0 (labeled "old control"), 9 for old control day 7 (labeled "old control d7"), and 10 for old CASIN day 7 (labeled "old + CASIN d7").Serum samples were simultaneously loaded for all cytokines probed and into all experimental arms. Some samples did not produce signals above background due to technical reasons and were excluded from statistical analysis. Bars represent mean + / - SEM. *p<0.05, **p<0.01 by one-way ANOVA and Tukey's multiple comparison test. (i) Biological age prediction based on DNA methylation profiles of blood cells from aged control and aged CASIN-treated mice 8–9 weeks after treatment. Experiments were repeated twice with cohorts of 5–6 animals per group (n=12 for control and 11 for CASIN). Bars represent mean + / - SEM. *p<0.05 by unpaired t-test analysis. For aged controls ("Aged Control") and "AgedCASIN," bars are displayed on the left for "biological age" and on the right for "chronological age." There is a difference of approximately 9 weeks between the biological age and chronological age of the "Aged" group. [Figure 2](a) PK analysis of CASIN in mouse serum using LC / MS / MS ion chromatography of 100 μL serum samples from CASIN-injected mice. (b) Standard curve of CASIN in mouse serum by LC / MS / MS. CASIN was added to serum at concentrations of 0, 0.5, 1.0, and 5.0 μM and subsequently analyzed. (c) Body weight in grams of mice included in the lifespan study described in Figure 1(a). (d, e) White blood cell (WBC) and red blood cell (RBC) counts of mice included in the lifespan study described in Figure 1(a). (f, h) Flow cytometry analysis of peripheral blood (PB) from mice in the lifespan study described in Figure 1(a). Data are plotted as the percentage of B220+, Cd3+, and Gr1+, Mac1+, and Gr1+Mac1+ cells among all white blood cells (WBCs). (i, k) Lymphocyte (Ly), neutrophil (NE), and monocyte (Mo) cell counts from mice in the lifespan study described in Figure 1(a). Data from Figure 2(c) to (k) are shown as boxplots showing the minimum to maximum values; n = 18 for controls (labeled "control aged" and represented by white boxes) and n = 17 for CASIN-treated animals (labeled "CASINaged" and represented by gray boxes). Days of analysis according to the scheme in Figure 1a. [Figure 3] Data from cytokine array analysis. Serum was collected from mice on day 0 (old control) and day 7 (old control and old CASIN) according to the scheme shown in Figure 1(a). Blood from young (10-week-old) C57BL / 6 females was used for the young control samples in the cytokine array. The number of experimental mice included was 7 for young control ("young control"), 27 for old control day 0 ("old control"), 9 for old control day 7 ("old control d7"), and 10 for old CASIN day 7 ("old + CASIN d7"). Serum samples were loaded simultaneously for all cytokines probed and in all experimental arms. Some samples did not produce signals above background due to technical reasons and were excluded from statistical analysis. Bars represent mean + / - SEM. *p<0.05, **p<0.01 by one-way ANOVA and Tukey's multiple comparison test. [Figure 4] Abstract showing that short-term systemic treatment of aged mice with a Cdc42-specific inhibitor (e.g., CASIN) and its associated effects include an extension of median and maximum lifespan, a reduction in inflammatory cytokines (e.g., INFγ, IL-1α, IL-1β), and dialing back (e.g., resetting) the epigenetic clock of DNA methylation levels as an indication of chronological age compared to biological age. [Figure 5] (A) Scheme of the experimental setup for analyzing vaccination responses. (B) Quantification of interferon-gamma-positive CD3+CD8+ T cells according to the protocol in Figure 5(A). (C) Quantification of splenic Kb / C93-100-dimer+CD8+ T cell frequency determined by flow cytometry according to the protocol in Figure 3(A). (D) Antibody titers after viral vaccination showing the effect of age and Cdc42-specific inhibitor treatment according to the protocol in Figure 3(A). DETAILED DESCRIPTION OF THE INVENTION

[0011] Age-related remodeling of the immune system impairs its functional integrity and contributes to morbidity and mortality in the elderly. contributes to increased mortality.

[0012] Age-related changes in immune system phenotype and function are primarily due to age-related hematopoietic stem cells (HSCs). HSC senescence is the result of altered function of the small RhoGTPase C. Until recently, the senescent HSC phenotype was largely mediated by increased DC42 activity. are governed by cell-intrinsic regulatory mechanisms that cannot be reversed by therapeutic intervention. However, new research has shown that HSC aging can be improved. Identifying Cdc42 activity as a pharmacological target for HSC aging These findings suggest a novel and important mechanistic role for Cdc42 activity. Pharmacological inhibition of elevated Cdc42 activity in SCs may rejuvenate senescent HSCs. There is a possibility.

[0013] Cdc42 is involved in multiple functions of eukaryotic cells, including actin cytoskeleton reorganization, cell polarity, and cell proliferation. Cdc42 is involved in diverse functions of the ATPase. It can be converted into an inactive GDP-bound state and an active GTP-bound state. Cycling between GDP-bound and GTP-bound states is essential for many different regulatory pathways. Its activity and therefore the level of Cdc42-GTP are tightly regulated by the protein. The bell is found in the blood of aged animals (e.g., humans) and in tissues such as the heart, brain, lungs, liver, bone marrow, spleen, and kidneys. Cdc42GT is significantly elevated in several tissues of aged C57BL / 6 animals. Pase-activating proteins (Cdc42GAP; p50RhoGAP or ARHGAP) 1) catalyzes the hydrolysis of Cdc42-bound GTP. Cdc42GAP is a ubiquitously expressed negative regulator of Cdc42. Genetic deletion of Cdc42GAP in mice (Cdc42GAP knockout) increased the levels of Cdc42-GTP in all tissues. This constitutive increase in Cdc42 activity in young mice is associated with several It affects tissues and leads to phenotypes such as premature aging that result in shortened lifespan.

[0014] Presented herein is a method for the treatment of inflammatory bowel disease by exposing a subject to a Cdc42-specific inhibitor. Regulate or increase the lifespan, survival time, lifespan, and / or healthspan of an elephant an immune system capable of mounting a strong immune response to vaccination These and other new aspects are discussed in This is explained in more detail below.

[0015] As described herein, where a range of values ​​is provided, the range may be any number of values ​​unless the context clearly dictates otherwise. Unless otherwise specified, each intervening value between the upper and lower limits of the range, up to one-tenth of the unit of the lower limit, is It is intended to be understood that any other stated value or intermediate value within the stated range is also included. Any value within these smaller ranges is included within the scope of the embodiments. may be included in smaller ranges, subject to any specifically excluded limits in the stated ranges. Where the stated range includes one or both of the limits, Ranges excluding both of those inclusive limits are also included in the embodiments. 1-6, if the whole is reported for a specific value, e.g., 1, 2, 3, 4, 5, 6, etc. Note that ranges can be enumerated from the entire set of integers mentioned above, such as 2-6, 3-5, 1-4, etc. It is intended.

[0016] Unless otherwise defined, technical and scientific terms used herein are defined by the principles to which this disclosure pertains. have the same meaning as commonly understood when read in light of this disclosure by one of ordinary skill in the art. Any methods and materials similar or equivalent to those described herein may also be used in practice. Although any method or material may be used in the practice or testing of the present invention, the preferred methods and materials are described herein. All publications mentioned in this document are expressly incorporated by reference in their entirety.

[0017] As used in this specification and the appended claims, the singular forms "a," "and," and "the" includes plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes a plurality of such methods, and reference to "a dosage" includes a plurality of such methods. A reference to a dose includes a reference to one or more doses and equivalents thereof known to those skilled in the art.

[0018] The terms "individual," "host," "subject," and "patient" refer to individuals who are involved in treatment, observation, and / or or animals that are the subject of experiments. "Animal" includes vertebrates. and invertebrates, such as fish, crustaceans, reptiles, birds, and especially mammals. "Mammals" include mice, rats, rabbits, guinea pigs, dogs, cats, sheep, and These include animals such as geese, cattle, horses, and primates (monkeys, chimpanzees, apes, etc.), especially humans. Not limited to these.

[0019] The term "about" or "approximately" refers to an acceptable range of a particular value as determined by one of ordinary skill in the art. within a reasonable error range, which may be due to how the value is measured or determined, e.g. It depends in part on the limitations of the system. For example, "about" may mean, according to the practice in the art, within 1 or more than one standard deviation. Alternatively, "about" can mean up to 20%, preferably at most 10%, more preferably at most 5%, even more preferably at most 1 It can also refer to a range of % or, more specifically, to a biological system or process. The term means within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value. Where specific values ​​are described in this application and claims, unless otherwise specified, , the term "about" should be construed to mean within an acceptable range of error for a particular value.

[0020] As used herein, the term "heterologous sequence or gene" refers to a heterologous sequence or gene that is present in a particular molecule. "A" refers to a nucleic acid (RNA or DNA) sequence that is not found in nature in association with the nucleic acid sequence. In this section, we will discuss some approaches that can be used to prepare inhibitors of Cdc42. We will explain in detail about Chi.

[0021] How to increase The embodiments disclosed herein comprise administering to a subject in need of treatment an effective amount of at least one Certain methods described herein involve administering a Cdc42-specific inhibitor to administering to a subject in need thereof an effective amount of at least one Cdc42-specific inhibitor. Extending the lifespan, survival time, life span, or health status of a subject, including It relates to a method for rolling out bread.

[0022] "Lifespan" is the expected lifespan of a subject based on the year the subject was born and their current age. It also refers to time. In addition, factors such as gender, genetics, lifestyle (smoking, exercise, activities of daily living, alcohol consumption, diet, self-care practices, social contacts, working patterns, etc.), culture, politics, religion These may include subject-specific demographics or determinants such as education, socio-economics, etc. 'Aging and Health' (2001), 01 / WHO / NMH / NP See H01.2.

[0023] "Survival time" refers to the expected time until a subject dies. Subject-specific demographics or decisions, such as education, lifestyle, culture, politics, religion, socio-economics, etc. This may include certain factors.

[0024] "Lifespan" refers to the period of time a subject is expected to remain at a particular age. subject-specific characteristics such as gender, genetics, lifestyle, culture, politics, religion, socio-economics, etc. May include demographics or determinants.

[0025] "Health span" refers to the expected length of time in a subject's life during which the subject is reasonably healthy. In some embodiments, the health of a subject refers to physical, mental, and social well-being, disease, and the like. and lack of frailty.

[0026] The "increase" referred to in the disclosed embodiments is in contrast to the actual increase experienced by a particular subject. In contrast, the term "expected increase" refers to the number of subjects who have achieved the desired results. To do this, you must wait for the target's lifespan, survival time, lifespan, or healthspan to expire. In a preferred embodiment, the expected increase is statistically significant, but the expected The increase may or may not be statistically significant. There are many ways to do this, for example, to calculate a "p-value." The thresholds for statistical significance were p-values ​​≤ 0.2, ≤ 0.15, ≤ 0.1, ≤ 0.05, ≤ 0.01, ≦0.005, about ≦0.2, about ≦0.15, about ≦0.1, about ≦0.05, about ≦0.01, or about ≦0.005. In some cases, the results may not be statistically significant. However, the results are still informative or suggest some given benefits. The degree of significance that may be attributed to the results of a determination is understood to be within the skill of an ordinary physician. It is understood.

[0027] In some embodiments, the expected lifespan, survival time, lifespan, or health of a subject is determined. The health span is the median predicted value for similarly situated subjects. The lifespan, survival time, lifespan, or healthspan of a person is the average predicted lifespan of similarly situated individuals. Similar subjects were randomly selected based on age, health, family history, or Cdc42 activity level. The determination may be based on any one or more factors, including but not limited to:

[0028] The expected increase is based on the subject's expected lifespan, survival time, lifespan, or health 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11% , 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% ,22%,23%,24%,25%,26%,27%,28%,29%,30%,approx. Any of the above percentages or a range bounded by any of the above percentages range (e.g., about 1% to 30%, about 5% to 25%, about 5% to 20%, about 5% to 15%, or is 1%~30%, 5%~25%, 5%~20%, 5%~15%, 1%~100%, 1% ~90%, 1%~80%, 1%~70%, 1%~60%, 1%~50%, 1%~40%, 1%~30%, 1%~20%, 1%~10%, 10%~100%, 10%~90%, 10 %~80%, 10%~70%, 10%~70%, 10%~60%, 10%~50%, 10 %~40%, 10%~30%, 10%~20%, 20%~100%, 20%~90%, 2 0%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 2 0%~30%, 30%~100%, 30%~90%, 30%~80%, 30%~70%, 30%~60%, 30%~50%, 30%~40%, 40%~100%, 40%~90% , 40%~80%, 40%~70%, 40%~60%, 40%~50%, 50%~100 %, 50%~90%, 50%~80%, 50%~70%, 50%~60%, 60%~10 0%, 60%~90%, 60%~80%, 60%~70%, 70%~100%, 70%~ 90%, 70%~80%, 80%~100%, 80%~90%, 90%~100%, and Any of the aforementioned percentage ranges (e.g., about 10% to 70%, about 30% to 60%) %, or about 50% to 70%).

[0029] In some embodiments, the expected increase is the expected lifespan, survival time, or life expectancy of the subject. The span, or number of years relative to the health span, is 1-20 years, 1-19 years, 1-1 8 years, 1~17 years, 1~16 years, 1~15 years, 1~14 years, 1~13 years, 1~12 years, 1 ~11 years, 1-10 years, 1-9 years, 1-8 years, 1-7 years, 1-6 years, 1-5 years, 1-4 years , 1-3 years, 1-2 years, 1 year, at least the aforementioned years (e.g., at least 1-10 years), or for approximately the aforementioned number of years (e.g., about 1-2 years or at least about 1-2 years).

[0030] In some embodiments, the expected increase is measured by the expected lifespan, survival time, life span, etc. For the period, or health span, it is a few days to a few months, which is 1 day to 1 year, 1 day to 11 Month, 1st-10th month, 1st-9th month, 1st-8th month, 1st-7th month, 1st-6th month, 1st ~5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, at least as mentioned above A range of several days to several months (e.g., at least 1 day to 11 months), or approximately the aforementioned several days to several months (e.g., about 1 day to 6 months or at least about 1 day to 6 months).

[0031] In some embodiments, the expected increase is the expected lifespan, survival time, or life expectancy of the subject. Span, or health span, is a number of weeks, which can be 1 week, 2 weeks, 3 weeks, 4 weeks. Weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks Weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks Weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks Weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks Weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or approximately any of the weeks mentioned above (e.g., about 15 weeks), or at least one of the aforementioned weeks (e.g., at least about 1 5 weeks), or a range enclosed by any two weeks in the preceding list (e.g., 2-30 weeks or is about 2-30 weeks, or at least about 2-30 weeks), 1-52 weeks, 2-50 weeks, 3-45 weeks, 4-40 weeks, 5-35 weeks, 6-30 weeks, 5-25 weeks, 6-20 weeks, 7-1 9 weeks, 8-18 weeks, 9-17 weeks, 10-16 weeks, 11-15 weeks, 12-14 weeks, at least Both in the aforementioned range of weeks (e.g., at least 6-20 weeks) or approximately in the aforementioned range of weeks (e.g., about 6 to 20 weeks or at least about 6 to 20 weeks).

[0032] In some embodiments, the expected increase is the expected lifespan, survival time, or life expectancy of the subject. Span, or health span, is a number of days, which can be 1 day, 2 days, 3 days, 4 days, 5 days, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, for any of the preceding days (e.g., about 15 days), for at least about any of the aforementioned weeks (e.g., at least about 15 days ), or a range bounded by any two of the preceding weeks (e.g., 2-30 days or approximately 2-3 0 days, or at least about 2-30 days).

[0033] The "reduction" or "decrease" referred to in the disclosed embodiments is not meant to be an "actual" or Refers to a "projected" decline or decrease. Actual or projected decline or decrease may be statistically significant. Although it may or may not be statistically significant, in preferred embodiments, any decrease or The decrease is statistically significant. There are many known methods for calculating statistical significance. In some embodiments, the statistical significance threshold is calculated as p Values ​​≦0.2, ≦0.15, ≦0.1, ≦0.05, ≦0.01, ≦0.005, approximately ≦0. 2. Approximately ≦0.15, approximately ≦0.1, approximately ≦0.05, approximately ≦0.01, or approximately ≦0.005 In some cases, the results may not be statistically significant, but the results are still informative. or suggests some given benefit. It is understood that the degree of significance is within the skill of an ordinary physician.

[0034] Immunization Method The embodiments disclosed herein comprise administering to a subject in need of immunization an effective amount of at least one and administering to the subject one or more immunization doses of a Cdc42-specific inhibitor of Surprisingly, direct pharmacological activity of Cdc42-specific inhibitors in subjects Direct intervention of this kind allows for a strong immune response upon challenge with an immunogen. HSCs were obtained from matched donors by immunization, purified, and then treated with a Cdc42-specific inhibitor. Pre-processing HSCs eliminates the need to transplant processed donor HSCs into transplant recipients Therefore, under some of the embodiments disclosed herein, Cdc42-specific inhibition The agent essentially acts as a type of adjuvant, modifying the subject's immune system and immune response. In some embodiments, the efficacy of immunization is enhanced by administering a Cdc42-specific antibody. The selective inhibitor is combined with the immunization dose prior to administration to the subject (e.g., the subject is administered the immunogen and a Cdc42-specific inhibitor). In embodiments, the immunization dose and the Cdc42-specific inhibitor are administered separately to the subject. It is administered in doses.

[0035] In some embodiments, the Cdc42-specific inhibitor is administered to a subject after one or more immunization doses. In another embodiment, the Cdc42-specific inhibitor is administered to a subject prior to receiving a The immunization regimen is administered to a subject simultaneously with a subject receiving one or more immunization regimens. May be administered by multiple administrations over a period of time (e.g., a single office visit by a physician). Alternatively, the co-administration can be carried out simultaneously or at about the same time.

[0036] Subjects who need to receive a Cdc42-specific inhibitor to improve their immune response should first The subject does not necessarily need to be identified before administering the immunization. For example, the subject may be identified before the first attempted They may be identified by exhibiting an inadequate response to immunization. In this case, the Cdc42-specific inhibitor is administered to the subject after the subject has received one or more immunization doses. can be.

[0037] In many cases, subjects do not receive sufficient immunity from a single immunization dose, and sufficient immunity is not conferred. Multiple immunizations are required before the vaccine is administered. and administering the first Cdc42-specific inhibitor to the subject. The subject receives a first immunization dose after administration of a selective inhibitor, and the subject receives a first immunization dose after administration of a selective inhibitor. Such a regimen involves administering a second immunization dose to a subject followed by one or more subsequent immunization doses. After receiving one dose, the subject may continue to receive a third immunization dose. ~10, 1~9, 1~8, 1~7, 1~6, 1~5, 1~4, 1~3, 2~10, 2~9 , 2~8, 2~7, 2~6, 2~5, 2~4, 2~3, 3~10, 3~9, 3~8, 3~ 7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5 ~10, 5~9, 5~8, 5~7, 5~6, 6~10, 6~9, 6~8, 6~7, 7~1 0, 7-9, 7-8, 8-10, 8-9, 9-10, or 2, 3, 4, 5, 6, 7, 8 , 9, or 10 total immunization doses for immunization against individual diseases. The Cdc42-specific inhibitor may be administered prior to the first immunization or after one or more subsequent immunizations. may be administered before

[0038] In many cases, the subject requires immunization against one or more diseases (e.g., the subject has a small (immunization against multiple diseases throughout childhood or adulthood). This is This may be due to later travel or lack of childhood immunization in the subject. The dc42-specific inhibitor is administered prior to the first immunization or when the subject is diagnosed with one or more diseases, or If immunized against multiple diseases, it may be administered before one or more subsequent immunization doses. Similarly, the first immunization and subsequent immunizations may be the same or different (e.g., (e.g., in strength, concentration, or immunogen) administered to a subject. The dc42-specific inhibitors may be the same or different.

[0039] In some cases, a period of time elapses between administering immunizing doses to the subject. In embodiments, the period between immunizations is about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about In some embodiments, the one or more The Cdc42-specific inhibitor is administered to the subject during the period between administration of the subject's immunization doses.

[0040] Subjects who would benefit from the administration of a Cdc42-specific inhibitor during immunization would have a healthy immune system. Alternatively, in some embodiments, the subject may have a healthy immune system. The subject's immune system may be susceptible to infection, particularly depending on the subject's age, the subject's medical condition, or the subject's disease. Treatment of a subject for a condition renders the immune system susceptible to infection.

[0041] Unless otherwise specified, the full scope of the term "immunization" includes the methods disclosed herein. Immunization can be passive or active. Passive immunization is the prior activation of the immune system. The synthesized elements are transferred to the person, so the body does not need to produce these elements itself. Antibodies can be used for passive immunization. Active immunization occurs when a person comes into contact with a microorganism. They can occur naturally, such as when the virus is weakened or when a person comes into contact with a part of the microorganism. However, the immunogen need not be a microorganism, for example, in some embodiments, Immunogens can be small molecules (e.g., nicotine) or macromolecules (e.g., proteins such as oncoproteins). protein, or hormones such as ghrelin).

[0042] As discussed above, immunizations are also vaccines, although immunizations are not necessarily so limited. Thus, in some embodiments, the immunization is not a vaccine. Some vaccines are recommended by the World Health Organization or the Centers for Disease Control and Prevention. In some embodiments, the immunization is a vaccine recommended by the medical community. In some embodiments, the vaccine is recommended by the Centers for Disease Control and Prevention. Vaccines are also approved by the World Health Organization, the Centers for Disease Control and Prevention, or the National Institutes of Health for administration to adults. In some embodiments, the vaccine is administered to children and In some embodiments, the disease affects adults disproportionately compared to adults. In the United States, vaccines are available for influenza, whooping cough, tetanus, diphtheria, shingles, and pneumonia. Coccal disease, human papillomavirus, meningococcal disease, hepatitis A, hepatitis B, chickenpox, measles , mumps, and rubella.

[0043] Subject Identification The embodiments disclosed herein provide a method for administering to a subject in need thereof a compound having a Cdc42-specific activity. administering an effective amount of at least one Cdc42-specific inhibitor, including a Cdc42 modulator, In some embodiments, not all subjects are candidates for such administration. In some cases, it may be desirable to identify a target for treatment, regardless of the severity of the condition. Patient selection is based on the usual training of a skilled physician. It is understood that the results will depend on many factors within the laboratory. Some embodiments include administering an effective amount of at least one Cdc42-specific inhibitor to a patient to inhibit lifespan. prolonging survival time, extending lifespan, or improving upon immunization The subject may be identified as one who would benefit from the treatment, based on the subject's age, current medical condition, current treatment, prescribed treatment, Prima1, Hsf4, or Kc of any subject depending on the methylation status of CpG sites within the ns1 gene, or any combination thereof , based on physiological factors specific to the subject, or in a preferred embodiment, based on the subject's Cdc4 2 activity in a subject's blood sample. Assays for determining Cdc42 activity in a subject are known in the art. For example, Mizukawa et al., Blood (2017) 130:1336- See 46.

[0044] In some embodiments, the physician administers an effective amount of at least one Cdc42-specific inhibitor. Relying on a combination of physiological factors in a given subject to identify targets for treatment with an anti-inflammatory agent As noted above, the age of the subject may be a factor in identifying a subject in need of treatment. For example, the subject can be elderly (e.g., an elderly human subject). In some embodiments, the elderly human subject is 50 or older, 51 or older, 52 or older, 53 or older Above, 54 and above, 55 and above, 56 and above, 57 and above, 58 and above, 59 and above, 60 and above, 61 and above Above, 62 and above, 63 and above, 64 and above, 65 and above, 66 and above, 67 and above, 68 and above, 69 and above Above, 70 and above, 71 and above, 72 and above, 73 and above, 74 and above, 75 and above, 76 and above, 77 and above above, 78 and above, 79 and above, 80 and above, or a range bounded by any of the aforementioned ages (e.g. For example, 50-80 years old or older, 50-70 years old or older, 50-60 years old or older, 55-75 years old or older, 55 years old or older ~75 years old and over, 55-70 years old and over, 55-65 years old and over, 60-70 years old and over, 52-71 years old The age range is 60-79 years or older, or 73-78 years or older.

[0045] In some embodiments, as discussed above, the subject is a human. The method is not limited to the treatment of humans, but is equally applicable to the treatment of mammals other than humans. In such instances where other mammals are being treated, patient selection should be performed by a regular trained veterinarian or laboratory technician. The results depend on many factors within the research scientist's laboratory.

[0046] Cdc42-specific inhibitors The embodiments disclosed herein include a compound comprising at least one Cdc42-specific inhibitor. In some embodiments, the present invention relates to compounds, compositions, pharmaceutical compositions, methods, uses, and kits. In this context, Cdc42-specific inhibitors include chemical inhibitors such as small molecules (e.g., CASIN). Small molecules can include, for example, molecules with a low molecular weight (e.g., a molecular weight of less than 2000 daltons). Additionally, Cdc42-specific inhibitors include siRNA molecules, antisense molecules, small RNAs (e.g., microRNAs) or modified nucleic acids, ribozymes, Antibodies (such as neutralizing antibodies), or polypeptides (e.g., dominant-negative peptides) Any type of inhibitor known to those skilled in the art can be used.

[0047] Another aspect of the embodiment relates to the regulation of biological pathways involving GTPases. Thus, some embodiments provide an effective amount of an activator, an effective amount of an activator for inhibiting the activity of Cdc42 GTPase. C, including compounds that specifically and / or selectively modulate The present invention relates to all aspects of regulating the activity of Cdc42 GTPase. Activities include GTP binding, GDP binding, GEF binding, GTPase activity, and integrin binding. , receptor or effector-like molecules (integrins, growth factor receptors, tyrosine kinases This includes coupling or binding of Cdc42 to other proteins (e.g., PI-3K, PIP-5K) Cdc42 activity can be modulated by increasing, decreasing, antagonizing, or promoting it. Regulation of Cdc42 can be measured by assays such as GTP hydrolysis and binding to GEFs. An effective amount is any amount that, when administered, modulates Cdc42 activity. Activity can be measured in cells, tissues, whole organisms, in situ, in vitro (test tubes, solid supports, etc.) The modulation can be performed in vivo, in vivo, or in any desired environment. In this study, an effective amount of a Cdc42-specific inhibitor is determined to be a dose that reduces Cdc42 activity to normal levels in a subject. In some embodiments, the effectiveness of a Cdc42-specific inhibitor is The effective dose reverses tubulin apolarity in cells. Cdc42 activity in blood precursor cells, such as hematopoietic cells, progenitor cells, or stem cells, is regulated by transcription factor 1 (TNF-α). In some embodiments, the effective amount of a Cdc42-specific inhibitor is Does not mobilize blood progenitor cells.

[0048] Other assays for Cdc42-mediated signaling are described, for example, in U.S. Pat. Nos. 41,851, 5,420,334, 5,436,128 and 5, This can be accomplished according to procedures known in the art, such as those described in US Pat. No. 4,822,954. all of which are incorporated herein by reference in their entirety where permitted. Furthermore, interactions between activators and G proteins such as Cdc42, e.g. For example, peptides that inhibit binding can be identified.

[0049] Methods for detecting inhibition of Cdc42 activity are available from Thermo Fisher Scientific. Active Cdc42 pulldown and and detection kits, as described in the Examples section below. and Asnaghi et al, Oncogene (2010) 29:2760 Detection of inhibition is known in the art through the incorporated documents of US Pat. No. 6,277,114. This may include comparing the inhibitory properties of the compound being tested with the inhibitory properties of one or more reference compounds. Such reference compounds may be, for example, CAS1N or other compounds described herein. could be.

[0050] By modulate, it is meant that the addition of an agent affects activity or binding. Binding or modulating activity includes inhibiting, blocking, preventing, increasing, enhancing, or promoting it. The binding or activation effect can be achieved in a specific way. It is not necessary to cross-link the drug to a GEF or GTPase, for example, through cross-linking between the drug and the GEF or GTPase. They can be competitive, noncompetitive, allosteric, or sterically hindered. Drugs are either activators or GTs. Drugs can act on either the Pase receptor or the receptor agonist. The presence or amount of binding may vary depending on the The method involves the detection of, for example, activities such as guanine nucleotide exchange, GTP hydrolysis, and oncogenic transformation. The activity stimulated or inhibited by the inhibitor can be determined by assaying the activity. Such assays are also described above or below and are known in the art. Drugs can be obtained and / or prepared from a variety of sources, including natural and synthetic. It can be, for example, amino acids, lipids, carbohydrates, organic molecules, nucleic acids, inorganic molecules, or can include mixtures thereof.

[0051] As is understood in the art, detecting modulation can be performed in vitro or in vivo. Examples of in vitro and in vivo methods are provided herein. Results from evaluating the inhibitory properties of the compounds provided herein can be measured, for example, by IC 50 , E.C. 50 , K. i or other standard terminology known in the art. Therefore, the assessments provided herein may be reported in terms that are understood to be accurate. and evaluating the results may include determining the inhibitory properties of the compound being tested. In some cases, evaluating the results also involves determining the inhibitory properties of the compound being tested. This also includes comparing the inhibitory properties of the above reference compounds. Such reference compounds can be, for example, It may be CASIN or other compounds described herein.

[0052] small molecule Small molecule inhibitors, as disclosed herein, specifically inhibit and / or inhibit Cdc42. Any type of small molecule known to those skilled in the art can be used to regulate or inhibit the activity of a protein. Many methods are known for identifying small molecule inhibitors, and small molecule inhibitors can be used. Commercial laboratories are available to screen for inhibitors. For example, chemicals , Merck® Research Laboratories (Rahway) Compounds can be obtained from the compound collections of companies such as Sigma-Aldrich, Inc., NJ, or similar companies. Automated robotic screening in 96-well plate format for Cdc42 For example, compounds can be screened for inhibition at about 50 M in DMSO. The 96-well plate assembly is performed using a 96-well plate assay. The matrix may contain the appropriate number of units of Cdc42 and the target (substrate). Compounds that cause more than 50% inhibition of Cdc42 activity are further diluted and tested. The concentration required for 50% inhibition of activity can be established by Therefore, the screening is performed on Cdc42 protein and one or more of its binding proteins. The screened compounds will include candidate inhibitors and disrupt Cdc42 target binding. The inhibitory effect of disrupting the cytotoxicity of Cdc42 can be assessed by ELISA using, for example, Cdc42 or a surface-immobilized target. Residual binding can be monitored using a type A assay, e.g., by binding to a reporter (e.g., an alkali). Cdc42 target molecules conjugated to phospholipase Cdc42 are detected using antibodies. Binding assays can be performed to detect Cdc42 and its binding targets and inhibitors. Surface plasmon resonance (SPR)-based interaction screening, or protein-protein interaction Other assays to screen for effects (e.g., yeast two-hybrid system, immunoassay) immunocapture experiments combined with precipitation, enzymatic or FACS detection) In some embodiments, the candidate Cdc42 inhibitors can be any of the compounds known in the art. for its ability to inhibit Cdc42 GTPase activity using a previously described assay. In another embodiment, the Cdc42 inhibitor can be any of the compounds known in the art. For example, the amount of GTP-bound Cdc42 compared to the amount of GDP-bound Cdc42 can be measured using assays that have been developed. The antibodies can be tested for their ability to reduce the amount of bound Cdc42.

[0053] In any of the embodiments described herein, the Cdc42-specific inhibitor, the C Inhibitors of the GTPase Cdc42, Inhibitors of the GTPase Cdc42, inhibitors, agents capable of inhibiting the GTPase Cdc42, or agents capable of inhibiting Cdc42 The specific inhibitors may be single enantiomers, mixtures of enantiomers, pharmaceutical and a compound of formula (I) as a commercially acceptable salt, solvate, or polymorph thereof, [ka] During the ceremony, Y is selected from the group consisting of -OR7, -NR8R9, and -NNR8R9; R7 is C 1~6 Alkyl, -(CH2) u C 3~7 Cycloalkyl, C 2~6 Arke Nill, C 1~6 Alkoxy, Hydroxy-C 1~6 Alkyl, phenyl, up to 5 full C substituted with Oro 1~6 Alkyl and C substituted with up to 5 fluoro 1~6 a alkoxy, 1~6 Alkyl, -(CH2) u C 3~7 Shik Roalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C1~6 Alkyl , phenyl, C substituted with up to 5 fluoro 1~6 Alkyl, and up to 5 full C substituted with Oro 1~6 Alkoxy is optionally substituted with halo, -CN, -OH, C1 ~6 Alkoxyl, heteroaryl, R 19 , and -OR 20 each from the group consisting of substituted with one or more independently selected substituents; R8 and R9 are each independently hydrogen or R 20 or R8 and R9, optionally together with the nitrogen to which they are attached, can be indolinyl, pyrrolidinyl, , piperidinyl, piperazinyl, or morpholinyl, each of which is selected from the group consisting of halo, cyano, No, Nitro, Hydroxy, C 1~6 Alkyl, (CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C 1~6 Alkyl, phenyl, Large 5 fluoro-substituted C 1~6 C1 substituted with alkyl and up to 5 fluoro ~6 and optionally substituted with one or more substituents each independently selected from the group consisting of: alkoxy; or R8 and R2 are joined together to form a ring; ~3 And Each R 20 is C 1~6 Alkyl, C 3~7 the group consisting of cycloalkyl, and phenyl wherein C is independently selected from 1~6 Alkyl, C 3~7 Cycloalkyl, and phenyl are each independently R21 and R 22 one or more substituents selected from the group consisting of optionally replaced by Each R 21 are independently selected from the group consisting of halo, cyano, nitro, and hydroxy. R, Each R 22 is separately C 1~6 Alkyl, C 1~6 Alkoxy-(CH2) u C 3~7 S Chloroalkyl, C 2~6 Alkenyl, Hydroxy C 1~6 Alkyl, R 19 AND -OR 20 and wherein each is selected from the group consisting of halo, cyano, nitro, hydroxy, C 1~ 6 alkyl, and C 1~6 each independently selected from the group consisting of alkoxy and optionally substituted with the above substituents, each u is independently 0, 1, 2, 3, or 4; R2 is hydrogen or C 1~6 Alkyl, C 3~7 Cycloalkyl, and phenoxy wherein C is selected from the group consisting of: 1~6 Alkyl, C 3~7 cycloalkyl, and Phenyl is independently selected from halo, cyano, nitro, hydroxy, and C 1~6 Alkyl, -(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, hydroxy Droxy-C 1~6 C substituted with alkyl, phenyl, and up to 5 fluoro 1~6 Al Kill, C substituted with up to 5 fluoro 1~6 Alkoxy and, each independently, halo Ro, cyano, nitro, hydroxy, C 1~6 Alkyl, and C 1~6 From alkoxy -O(CH2) optionally substituted with one or more substituents selected from the group u From phenyl or R8 and R2 are optionally substituted with one or more substituents selected from the group consisting of Alkyl C that joins together as a ring 1~3 And R3, R4, R5 and R6 are each independently hydrogen, halo, cyano, nitro, hydroxyl Roxi, C 1~6 Alkyl, (CH2) u C 3~7 Cycloalkyl, -O(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C 1~ C substituted with 6 alkyl, phenyl, and up to 5 fluoro 1~6 Alkyl, and max. Five fluoro-substituted C 1~6 alkoxy, wherein C 1~6 Alkyl, (CH2) u C 3~7 Cycloalkyl, -O(CH2) u C 3~7 Cycloal Kill, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C 1~6 Alkyl and and phenyl each optionally have one or more R 23 is replaced by Each R 23 are independently halo, cyano, nitro, hydroxy, C 1~6 Alkyl, -(C H2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6Alkoxy, hydroxy C-C 1~6 C substituted with alkyl, phenyl, and up to 5 fluoro 1~6 Alkyl, and C substituted with up to five fluoro 1~6 alkoxy, The phenyl group can be substituted with halo, cyano, nitro, hydroxy, C 1~6 Alkyl, -(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Hydroxy-C1 ~6 Alkyl, substituted with up to 5 fluoro 1~6 Alkyl, and up to 5 full C substituted with Oro 1~6 one or more substituted independently selected from the group consisting of alkoxy optionally substituted with a group, Each R 19 are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups. C replaced by 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy is an aryl group, Each R 20 are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups. C replaced by 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy is hydrogen or aryl, When Y is NR8R9, R8 and R2 may optionally be joined together to form a ring. Bonding alkyl C 1~3 However, However, R8 and R2 are linked together to form a ring. 1~3 became provided that, in this case, R4 is not substituted with hydroxyl.

[0054] In some embodiments, one, two, or three of R3, R4, R5, and R6 One is not hydrogen.

[0055] R4 is C 1~6 Alkyl, -(CH2) u C 3~7 Cycloalkyl, -O(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, phenyl, max Five fluoro-substituted C 1~6 Alkyl and up to 5 fluoro substituted C 1~6 alkoxy, wherein C 1~6 Alkyl, -(CH2) u C 3~7 Cycloalkyl, -O(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl , C 1~6 Alkoxy and phenyl are each optionally substituted with haloC 1~6 Alkyl, -(CH 2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, hydroxy -C 1~6 C substituted with alkyl, phenyl, and up to 5 fluoro 1~6 Alkyl, and up to five fluoro-substituted C 1~6 Independently selected from the group consisting of alkoxy The group is substituted with one or more substituents selected from the group consisting of aryl, ...

[0056] In some embodiments, Y is -NR8R9, where R8 is hydrogen and R9 is hydroxyl. Roxi, R 19 AND -OR 20 one or more independently selected from the group consisting of C optionally substituted with substituents 1~6 alkyl, and each R 19 are independently halo, cyano , C substituted with up to five fluoro 1~6 Alkyl and up to 5 fluoro substituted C 1~6 one or more substituents each independently selected from the group consisting of alkoxy and each R is phenyl optionally substituted with 20 are independently halo, cyano, nitro, and hydro C substituted with up to 5 fluoro 1~6 Alkyl, and up to 5 fluoro C replaced with 1~6 one or more independently selected from the group consisting of alkoxy It is oxygen or phenyl optionally substituted with a substituent.

[0057] In some embodiments, each R 19 independently, halo, C 1~6 alkyl, and C 1~6 and optionally one or more substituents each independently selected from the group consisting of alkoxy. and each R 20 independently, halo, C 1~6 Alkyl, and C 1~6 and optionally one or more substituents each independently selected from the group consisting of alkoxy; It is a substituted phenyl.

[0058] In some embodiments, R2 and R8 are oxygen.

[0059] In some embodiments, Y is -NR8R9, and R8 and R2 together form a ring. C 1~3 It becomes alkyl.

[0060] In some embodiments, R9 is hydrogen.

[0061] In some embodiments, R is hydroxy, R 19 -OR 20 Consists of C optionally substituted with one or more substituents each independently selected from the group 1~6 Archi It is. Each R 19 are independently C optionally substituted with halo, cyano, or up to five fluoro; 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 The group consisting of alkoxy and Each R 20 are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups. C replaced by 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy The alkyl group is hydrogen or phenyl.

[0062] In some embodiments, R9 is hydrogen or C 1~6 alkyl and hydroxy Sill, R 19 AND -OR 20 one or more groups independently selected from the group consisting of Optionally substituted with substituents.

[0063] Each R 19are independently C optionally substituted with halo, cyano, or up to five fluoro; 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 The group consisting of alkoxy and Each R 20 are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups. C replaced by 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy The alkyl group is hydrogen or phenyl.

[0064] In some embodiments, R4 is C 1~6 Alkyl, -(CH2) u C 3~7 S Chloroalkyl, -O(CH2) u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~ C substituted with 6 alkoxy, phenyl, and up to 5 fluoro 1~6 Alkyl, and most Large 5 fluoro-substituted C 1~6 alkoxy, wherein C 1~ 6 alkyl, -(CH2) u C 3~7 Cycloalkyl, -O(CH2) u C 3~7 Cyclo Alkyl, C 2~6 Alkenyl, C 1~6 Alkoxy and phenyl are each optionally and one or more R 23 Each R is replaced by 23 independently, halo, C 1~6 Alkyl, -( CH2)u C 3~7 Cycloalkyl, C 2~6 Alkenyl, C 1~6 Alkoxy, Pheny C, substituted with up to five fluoro 1~6 Alkyl and up to 5 fluoro Replaced C 1~6 substituted with substituents independently selected from the group consisting of alkoxy; Phenyl, halo, C 1~6 Alkyl, -(CH2) u C 3~7 Cycloalkyl, C 2~ 6 Alkenyl, C 1~6 Alkoxy, C substituted with up to 5 fluoro 1~6 Alkyl , and up to five fluoro-substituted C 1~6 each independently selected from the group consisting of alkoxy; Optionally substituted with one or more substituents selected arbitrarily.

[0065] In some embodiments, R4 is C 1~6 Alkyl, C 3~7 cycloalkyl, -OC 3~7 Cycloalkyl, phenyl, C substituted with up to 5 fluoro 1~6 Al Kill, and up to five fluoro-substituted C 1~6 Selected from the group consisting of alkoxy , wherein the phenyl is halo, C 1~6 Alkyl, C 1~6 Alkoxy, up to 5 fluoro C replaced with 1~6 Alkyl and C substituted with up to 5 fluoro 1~6 Arco and optionally substituted with one or more substituents each independently selected from the group consisting of: hydroxy;

[0066] In some embodiments, Y can be -NR8R9, where R8 and R2 together are -NR8R9. C linked together as a ring 1~3 It becomes alkyl.

[0067] In some embodiments, R2 is hydrogen or C 1~6 Alkyl, C3 ~7 cycloalkyl, and phenyl, wherein C 1~6 Alkyl is , optionally substituted with one or more halo.

[0068] In some embodiments, R2 is hydrogen.

[0069] In some embodiments, R9 is hydrogen or C 1~6 alkyl and hydro Kisil, R 19 AND -OR 20 one or more independently selected from the group consisting of optionally substituted with substituents, Each R 19 are independently C optionally substituted with halo, cyano, or up to five fluoro; 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 The group consisting of alkoxy and Each R 20 are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups. C replaced by 1~6 C optionally substituted with alkyl and up to five fluoro 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy The alkyl group is hydrogen or phenyl.

[0070] In some embodiments, the compound of formula (I) is selected from the group consisting of: [ka]

[0071] In some embodiments, the compound of formula (I) is CASIN: [ka] or a pharmaceutically acceptable salt thereof.

[0072] The term "ester" refers to an ester of the formula -(R) n -COOR', wherein R and R' are alkyl, cycloalkyl, aryl, heteroaryl (through the ring carbons) and heteroaryl (attached via a ring carbon). where n is 0 or 1.

[0073] An "amide" is an amide of the formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R' wherein R and R' are alkyl, cycloalkyl, aryl, , heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon) and n is 0 or 1. The amide is attached to a molecule of the invention. The compound may be an amino acid or peptide molecule, thereby forming a prodrug.

[0074] Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention may be converted to an ester The procedures and characteristics used to achieve this goal can be Certain groups are known to those skilled in the art and are described in Greene and Wuts, Protecti ve Groups in Organic Synthesis, 3rd Edition, John readily found in reference sources such as Wiley & Sons, New York, NY, 1999. and is incorporated herein in its entirety.

[0075] As used herein, the terms "protecting group" and "protecting groups" refer to existing groups in a molecule. any atom or group added to a molecule to prevent it from undergoing undesired chemical reactions Examples of protecting group moieties are given in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis,3 .Ed.John Wiley & Sons, 1999, and JFWMcOmi e,Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are incorporated by reference. The protecting group moiety is stable to the applied reaction conditions and is incorporated herein by reference. Selected to be easily removed at a convenient stage using methodologies known in the art A non-limiting list of protecting groups includes benzyl, substituted benzyl; alkyl carbonyl (e.g., t-butoxycarbonyl (BOC)); arylalkylcarbonyl aryls (e.g., benzyloxycarbonyl, benzoyl); substituted methyl ethers (e.g., Methoxymethyl ether; Substituted ethyl ether; Substituted benzyl ether; Tetrahydro Pyranyl ethers; silyl ethers (e.g., trimethylsilyl, triethylsilyl, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl esters (e.g., benzoates); carbonates (e.g., methoxymethyl carbonates) sulfonates (e.g., tosylates, mesylates); acyclic ketals (e.g., dimethyl cyclic ketals (e.g., 1,3-dioxane or 1,3-dioxolane) ;Acyclic acetals;Cyclic acetals;Acyclic hemiacetals;Cyclic hemiacetals; and cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane). It can be enjoyed.

[0076] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because they may be easier to administer than the drug. For example, it may be bioavailable by oral administration, but the parent may not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Examples of prodrugs include, but are not limited to, those that cross cell membranes where water solubility is detrimental to mobility. Compounds of the invention administered as esters ("prodrugs") to enhance delivery of It can then be a carboxylic acid that is the active substance once inside the cell where water solubility is beneficial. Further examples of prodrugs are short peptides bonded to an acid group. (polyamino acids) where the peptide is metabolized to reveal the active moiety.

[0077] The term "aromatic" refers to a group of compounds having at least one ring with a conjugated pi-electron system and that are carbocyclic. Both aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine) The term refers to aromatic groups containing monocyclic or fused-ring polycyclic (i.e., adjacent carbon atoms). The term "carbocyclic" includes groups that share one or more rings. It refers to a ring structure closed by bonds, in which all atoms forming the main chain of the ring are carbon atoms. Therefore, the term refers to heterocycles whose ring backbone contains at least one atom different from carbon. The term "heteroaromatic ring" refers to an aromatic ring containing at least one heterocyclic ring. Refers to the group.

[0078] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, meaning that it does not react with an alkene or alkyne moiety. The alkyl moiety may also be an "unsaturated alkyl" moiety. This means that it contains at least one alkene or alkyne moiety. The "alkene" moiety contains at least two carbon atoms and at least one carbon-carbon double bond. an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least Refers to a group consisting of one carbon-carbon triple bond. The alkyl portion may be saturated or unsaturated. It may be branched, straight chain, or cyclic.

[0079] An alkyl group can have 1 to 20 carbon atoms (wherever it appears herein, A numeric range such as "1 to 20" refers to each integer in the given range. For example, "1 to 20 "Carbon atoms" refers to alkyl groups with one carbon atom, two carbon atoms, three carbon atoms, etc. However, in the definition of the present invention, a numerical range is specified. (This also applies to occurrences of the term "alkyl" where the term is not present). An alkyl group also has 1 to 10 carbon atoms. The alkyl group can also be a medium alkyl having 1 to 5 carbon atoms. The alkyl group of the compound of the present invention may be a lower alkyl having a C1 to C4 alkyl group. By way of example only, "C1-C4 alkyl" or similar designation may be used. "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

[0080] The alkyl group may be substituted or unsubstituted. If substituted, the substituent is a cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy thio, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbo Nyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiamine Ocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C -carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitrato silyl, trihalomethanesulfonyl, and amino (mono- and di-substituted amino groups) and one or more protected derivatives thereof, Typical alkyl groups include methyl, ethyl, propyl, isopropyl, and butyl. , isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. However, this is not limited to the following. Whenever a substituent is described as being "optionally substituted," However, that substituent can be substituted with one of the above substituents.

[0081] The substituent "R" appearing alone without a number designation is hydrogen, alkyl, cycloalkyl, aryl, or Heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon) ) is a substituent selected from the group consisting of:

[0082] An "O-carboxy" group refers to a RC(=O)O- group, where R is as defined herein. This is as it should be.

[0083] A "C-carboxy" group refers to a -C(=O)OR group, where R is as defined herein. This is as it should be.

[0084] An "acetyl" group refers to a -C(=O)CH3 group.

[0085] A "trihalomethanesulfonyl" group refers to a X3CS(=O)2- group where X is a halo This is Gen.

[0086] A "cyano" group refers to a -CN group.

[0087] An "isocyanate" group refers to an --NCO group.

[0088] A "thiocyanate" group refers to a -CNS group.

[0089] An "isothiocyanato" group refers to a -NCS group.

[0090] A "sulfinyl" group refers to a -S(=O)-R group, where R is defined herein.

[0091] An "S-sulfonamido" group refers to a -S(=O)NR group, where R is defined herein. It is being done.

[0092] An "N-sulfonamido" group refers to an RS(=O)2NH- group, where R is as defined herein. It is being done.

[0093] A "trihalomethanesulfonamide" group is a group represented by XCS(= 0)NR— group, where X and R are defined herein.

[0094] An "O-carbamyl" group refers to an -OC(=O)-N(R)2 group, where R is as defined herein. is defined.

[0095] An "N-carbamyl" group refers to an ROC(=O)NH- group, where R is as defined herein. There are.

[0096] An "O-thiocarbamyl" group refers to an -OC(=S)-N(R) group, where R is as defined herein. is defined as:

[0097] An "N-thiocarbamyl" group refers to an ROC(=S)NH- group, where R is as defined herein. It is being done.

[0098] A "C-amido" group refers to a -C(=O)-N(R) group, where R is defined herein. There are.

[0099] An "N-amido" group refers to a RC(=O)NH- group, where R is defined herein.

[0100] The term "perhaloalkyl" refers to alkyl groups in which all hydrogen atoms have been replaced with halogen atoms. It refers to an alkyl group.

[0101] The term "acylalkyl" refers to the group RC(=O)R'-, where R is as defined herein. where R' is a diradical alkylene group. Examples of acylalkyl include , CH3C(=O)CH2-, CH3C(=O)CH2CH2-, CH3CH2C(=O )CH2CH2-, CH3C(=O)CH2CH2CH2-, etc. Not limited.

[0102] Unless otherwise specified, when a substituent is deemed to be "optionally substituted," the substituent may be substituted with a silyl group. cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryl Aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, Thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocal Bamylic, C-Amido, N-Amido, S-Sulfonamide, N-Sulfonamide, C-Carboxylic O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, chloro aryl, trihalomethanesulfonyl, and amino (including mono- and di-substituted amino groups) and protected derivatives thereof. Protecting groups that can form protective derivatives of the above substituents include: These methods are known to those skilled in the art and can be found in references such as Green and Wuts, supra. do.

[0103] In the present context, the term "cycloalkyl" refers to cycloalkyl groups containing only 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 It is intended to cover rings of 6, 7, 8 or more members. Cycloalkyl is optionally Optionally, contain one or more unsaturated bonds positioned in such a way that no aromatic pi-electron system occurs Some examples of "cycloalkyl" include the carbocycles cyclopropane, cyclobutane, cyclopentane, cyclopentane, cyclopentane-1, cyclopentane-2, cyclopentane-3, cyclopentane-4, cyclopentane-5, cyclopentane-6, cyclopentane-7, cyclopentane-8, cyclopentane-9, cyclopentane-10, cyclopentane-11, cyclopentane-12, cyclopentane-13 ethane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclo Hexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane , or cycloheptene.

[0104] As used herein, a "heterocyclyl" refers to a group having at least one heterocyclic ring system. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen. A heterocyclyl may contain multiple fused rings. A heterocyclyl may contain at least one fused ring in the ring system. They can have any degree of saturation, as long as one ring is not aromatic. The alkyl group may be substituted or unsubstituted and may have any available valence, preferably any available valence. The heterocyclic ring is preferably a 5- or 6-membered ring. In a 6-membered monocyclic heterocycle, the heteroatoms are 1 to 3 oxygen, sulfur, and If the heterocycle is 5-membered, it is preferably selected from oxygen, sulfur, and nitrogen. It has one or two heteroatoms.

[0105] The heterocyclyl may further contain one or more carbonyl or thiocarbonyl functional groups. The definitions can be expanded to include lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like. This includes oxo and thio systems such as mate.

[0106] Some examples of "heterocyclyl" include tetrahydrothiopyran, 4H-pyran, tetrahydrothio ... Trihydropyran, piperidine, 1,3-dioxane, 1,3-dioxane, 1,4-di Oxane, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiane Yne, 1,4-oxathiane, tetrahydrofuran-1,4-thiazine, 2H-1,2- Oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, di Xopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexa Hydro-1,3,5-triazine, tetrahydrofuran, pyrroline, pyrrolidine, pyrolyl Don, pyrrolidione, pyrazoline, pyrazolidine, imidazolidine, imidazolidine, 1 ,3-dioxane, 1,3-dioxane, 1,3-dithiol, 1,3-dithiolane, Soxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, Including, but not limited to, thiazolines, thiazolidines, and 1,3-oxathiolanes The point of attachment of the heterocyclic radical is at the nitrogen heteroatom or at the It can be via a carbon atom.

[0107] In the present context, the term "aryl" means a carbocyclic aromatic ring or ring system. Additionally, the term "aryl" refers to a group consisting of at least two aryl rings. or at least one aryl and at least one C 3~8 -cycloalkyl Some examples of "aryl" rings include fused ring systems that share at least one chemical bond. is an optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetraphenyl Examples of aryl include aryl, fluorenyl, indenyl, and indanyl. The term "heterocyclic ring" refers to a ring that is attached via one of the ring-forming carbon atoms and is optionally heterocyclic. Acrylic, heteroaryl, halo, hydroxy, amino, cyano, nitro, alkylamido , Acyl, C 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C1 ~6 Aminoalkyl, C 1~6 Alkylamino, alkylsulfenyl, alkylsulf is selected from phenyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl; The aryl group is an aromatic group containing a benzenoid group having one or more substituents. and / or meta positions. In other embodiments, the aryl group is Representative examples of aryl groups include phenyl, 3-halophenyl, and the like. , 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl phenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxy Phenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl 3-cyanophenyl phenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxy Dimethylphenyl, trifluoromethylphenyl, alkoxyphenyl, 4-morpholine -4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4 -triazolylphenyl, and 4-(2-oxopyrrolidin-1-yl)phenyl These include, but are not limited to:

[0108] As used herein, the term "heteroaryl" refers to a group of rings having one or more heteroaryl groups attached to the ring backbone. means an aromatic radical having a heteroatom (e.g., oxygen, sulfur, or nitrogen) and a single It may contain a ring (e.g., pyridine) or multiple condensed rings (e.g., quinoline). The aryl group can have one or more substituents, each of which independently includes halo, hydro, oxy, amino, cyano, nitro, cycloalkyl, haloalkyl, aryl, heterocyclo Aryl, mercapto, alkylamide, acyl, C 1~6 -alkoxy, C 1~6 -Arki Lu, C 1~6 -hydroxyalkyl, C 1~6 Aminoalkyl, C 1~6-Alkylamine No, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl Representative examples of heteroaryl groups include fluoromethyl, fluoromethyl, and trifluoromethyl. Orchid, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole , oxazole, benzoxazole, isoxazole, benzisoxazole, thiazo benzothiazole, isothiazole, imidazole, benzimidazole, pyrazoline benzophenone, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidin amines, purines and pyrazines, furazans, 1,2,3-oxadiazoles, 1,2,3-thiazol- Azoles, 1,2,4-thiazoles, triazoles, benzotriazoles, pteridines, Fenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, Optionally substituted derivatives of talazine, quinazoline, and quinoxaline are included, In some embodiments, the substituents are halo, hydroxy, cyclohexyl ... That, OC 1~6 -Alkyl, C 1~6 -Alkyl, Hydroxy-C 1~6 -Alkyl , amino-C 1~6 -alkyl.

[0109] antisense molecules In some embodiments, the Cdc42-specific inhibitor may be an antisense molecule. The term "antisense" (AS) or "antisense fragment" refers to an inhibitory Polynucleotide fragments (deoxyribonucleotides) with specific antisense activity , ribonucleotides, or a mixture of both), which refers to the corresponding This results in a decrease in expression of the endogenous genomic copy of the gene. The target gene is then hybridized to the target gene. A polynucleotide containing consecutive nucleotides of sufficient length and sequence homology to a sequence Many reviews have been published on the main aspects of antisense (AS) technology and its enormous potential. It covers a wide range of therapeutic possibilities (e.g., Aboul-Fadl T., CurrMed. Chem.2005;12(19):2193-214;Crooke ST,Curr Mol.Med.2004August;4(5):465-87;Crooke S T,Annu Rev Med.2004;55:61-95;Vacek M et al.,Cell Mol Life Sci.2003 May;60(5):825 -33;Cho-ChungYS,Arch Pharm Res.2003March ;26(3):183-91;Moreira JN et al.,Rev Rec ent Clin Trials 2006 Sep;1(3):217-35) The chemical nature of this technique (Crooke, 1995; Uhlmann et al., 1999) 990), cellular (Wagner, 1994) and therapeutic (Hanania, et al , 1995; Scanlon, et al, 1995; Gewirtz, 1993) aspects Further reviews are available. Antisense intervention in the expression of specific genes is This can be achieved by using synthetic AS oligonucleotide sequences (e.g., Lefebvre-d'Hellencourt et al, 1995; Agrawa l, 1996; see LevLehman et al, 1997).

[0110] AS oligonucleotide sequences can be short sequences of DNA, usually 15-mer to 3-mer. Although it is a 0-mer, it complements the target mRNA of interest to form an RNA:AS duplex They can be as small as a 7-mer designed to 996). This duplex formation regulates the processing, splicing, and transport of the associated mRNA. Furthermore, certain AS nucleotide sequences may interfere with the target mRNA. When hybridized with NA, it induces cellular RNase H activity, leading to mRNA degradation. (Calabretta et al., 1996 Semin Oncol. 23 (1):78-87). In this case, RNase H cleaves the double-stranded RNA component, releasing AS. It may be released to further hybridize with additional molecules of target RNA. The mechanism is that AS interacts with genomic DNA to form a triple helix, rendering it transcriptionally inactive. There is a possibility that this will happen.

[0111] The sequence target segments of antisense oligonucleotides are those whose sequences match those of their complementary templates. exhibiting appropriate energy-related properties important for oligonucleotide duplex formation with the plate; Selected to show low potential for self-dimerization or self-complementarity (Anazo do et al., 1996). For example, the computer program OLIGO (registered (trademark) (Primer Analysis Software, version 3.4) was used. This is used to determine the melting temperature, free energy properties of the antisense sequence, and to identify potential self-dimers. The program can estimate the somatopoietic and self-complementary characteristics of these two It allows the determination of a qualitative estimate of the parameters (potential self-dimerization and self-complementarity) and provides an indication of "not potential" or "some potential" or "essentially complete potential" This program usually provides a solution where there is no potential for these parameters. A target segment is selected that is estimated to be As is known in the art, a segment with "multiple possibilities" can be used. A balance of data is used for selection. In addition, oligonucleotides can also be used to identify analogue substitutions. It is selected as needed so as not to substantially affect functionality.

[0112] Phosphorothioate antisense oligonucleotides are generally effective in animals. It showed no significant toxicity at the concentrations and had a sufficient pharmacodynamic half-life (Agarwal et al. l., 1996), nuclease resistant. Antisense-induced functions related to cell development The loss phenotype is due to the loss of glial fibrillary acidic protein (GFAP), a regulator of tectal plate formation in chickens. establishment (Galileo et al., 1991), and neuroectodermal culture (colony formation) Cellular heterogeneity in epithelial and neuroblastic cells (which differ in viability, tumorigenicity, and adhesion) It has been shown that the N-myc protein is responsible for the maintenance of the l., 1990; Whitesell et al., 1991). Mitogens and Antisense oligonucleotides of basic fibroblast growth factor (bFgF) have angiogenic properties. Retinoic acid inhibition inhibited 80% of glioma cell growth in a saturable and specific manner ( Morrison, 1991). Because of their hydrophobicity, antisense oligonucleotides It interacts well with phospholipid membranes (Akhter et al., 1991). Following interaction with the membrane, they undergo saturable mechanisms that are predicted to involve specific receptors. (Yakubov et al., 1989) in living cells. transported to the saccharin (Loke et al., 1989).

[0113] siRNA In other embodiments, the Cdc42-specific inhibitor is a "small interfering RNA" (siRNA). siRNA can be a gene / mRNA of its endogenous cellular counterpart (e.g., Cd c42) is an RNA molecule that reduces or silences (prevents) the expression of this gene. The term is understood to include "RNA interference" (RNAi). Small interfering RNA (siRNA, e.g., short hairpin RNA (shRNA)) refers to the process of sequence-specific post-transcriptional gene silencing in mammals mediated by (Fire et al., 1998, Nature 391, 806). The corresponding process is generally called specific post-transcriptional gene silencing or RNA silencing. The RNA interference response is called sedation, also called sedation in fungi. A type of RNA that mediates the cleavage of single-stranded RNA with a sequence complementary to the antisense strand of the strand, generally A siRNA-containing endonuclease called RISC-induced silencing complex (RISC) Cleavage of the target RNA occurs relative to the antisense strand of the siRNA duplex. It can occur in the middle of the complementary region (Elbashir et al. 2001, Genes Dev.,15,188). Recent information on these terms and proposed mechanisms Regarding Bernstein E., Denli AM., Hannon GJ: The rest is silence.RNA.2001 November;7(11): 1509-21; and Nishikura K.: Ashortprimeron RN Ai:RNA-directed RNA polymerase acts as a key catalyst.Cell.2001 November16;107(4 ):415-8.

[0114] RNAi is an efficient method for inactivating genes (Nature Rev iews,2002,v.3,p.737-47;Nature,2002,v.418 , pp. 244-51). One method is to detect the entry of dsRNA species into specific protein complexes. It is based on the ability of ATP to bind to complementary cellular RNA, where it targets and specifically degrades it. Specifically, dsRNA is degraded by type III RNases (DICER, Drosha, etc.). The nucleotide sequence is then digested into short (17-29 bp) inhibitory RNAs (siRNAs) (Nature, 2001,v.409,p.363-6;Nature,2003,425,p.415 -9). These fragments and complementary mRNAs are then transduced into specific RISC protein complexes. The whole process is initiated by endonucleolytic cleavage of the target mRNA. This is realized (Nature Reviews, 2002, v.3, p.737-47; C urr Opin Mol.Ther.2003June;5(3):217-24).

[0115] For disclosures regarding methods for designing and preparing siRNAs against known genes, see For example, ChalkAM, WahlestedtC, Sonnhammer EL.20 04 Jun.18;319(1):264-74;Sioud M,Leirdal M.,Methods Mol.Biol.2004;252:457-69;Leve nkova N,GuQ,RuxJJ.2004 Feb.12;20(3):430- 2; and Ui-Tei K, Naito Y, Takahashi F, Haraguchi T, Ohki-Hamazaki H, Juni A, Ueda R, Saigo K. ,Nucleic Acids Res.2004Feb.9;32(3):936-4 See PCT publications WO2004 / 015107 (Atugen) and WO02 / 44321 (Tuschl et al.), also Chiu YL, Rana TM RNA 2003September;9(9):1034-48 and USP at. Nos. 5,898,031 and 6,107,094 (Crooke) for production of modified / more stable siRNA See also s.

[0116] A DNA-based vector capable of producing siRNA within cells has been developed. In general, transcription of short hairpin RNAs is efficient in cells to form siRNAs. (e.g., Paddison et al. PNAS 2002, 99:1443- 1448;Paddison et al.Genes&Dev 2002,16:94 8-958; Sui et al. PNAS2002,8:5515-5520; and Brummelkamp et al.Science2002,296:550-55 3). These reports have identified numerous endogenously and exogenously expressed genes. describes a method for generating siRNA that can specifically target a gene.

[0117] For methods related to siRNA delivery, see, for example, Shen et al. (FEB Sletters539:111-114(2003)),Xia et al.,Na tureBiotechnology20:1006-1010(2002),Reic h et al.,MolecularVision9:210-216(2003), Sorensen et al.(J.Mol.Biol.327:761-766(2 003), Lewis et al., NatureGenetics32:107-1 08(2002) and Simeoni et al., Nucleic Acids Research 31,11:2717-2724(2003). RNA has recently been used successfully for inhibition in primates. For more information, see For example, Tolentino et al., Retina 24(1) February See 2004 pp132-138.

[0118] In some embodiments, oligoribonucleic acid according to embodiments disclosed herein The nucleotides include modified siRNAs. In various embodiments, the siRNAs are and a second strand, whereby the first strand is approximately the same as the target nucleic acid. A ribonucleotide sequence at least partially complementary to 18 to about 40 consecutive nucleotides. the second strand comprises a sequence of ribonucleotides that are at least partially complementary to the first strand. wherein the first strand and / or the second strand has a modification at the 2' position of the sugar moiety. ribonucleotides, thereby forming a chain of modified ribonucleotides within each strand. Each group is flanked on one or both sides by a group of adjacent ribonucleotides, thereby Each ribonucleotide forming a group of adjacent ribonucleotides is an unmodified ribonucleoside. a ribonucleic acid having a modification different from the modification of a group of ribonucleotides or modified ribonucleotides are selected from the following:

[0119] Ribozymes In some embodiments, the Cdc42-specific inhibitor may be a ribozyme. The term "ribozyme" refers to a molecule that has RNA catalytic ability and cleaves a specific site in a target RNA. According to embodiments disclosed herein, a ribozyme that cleaves mRNA is Immunoglobulins (e.g., Cdc42 mRNA) can be used as inhibitors. This may be necessary when chemotherapy is limited by stoichiometric considerations (Sa rver et al.,1990,GeneRegulationandAids,p Next, we used ribozymes to target genes associated with bone marrow disease. The number of RNA molecules cleaved by a ribozyme can be determined by probability chemistry. This is higher than expected (Hampel and Tritz, 1989; Uhl enbeck, 1987).

[0120] Ribozymes catalyze the cleavage of phosphodiester bonds in RNA. Group I introns , RNaseP, hepatitis delta virus ribozyme, hammerhead ribozyme, and Originally derived from the negative strand of tobacco ringspot virus satellite RNA (sTRSV), Several structural families of ribozymes have been identified, including the apin ribozymes (Sul Livan, 1994; U.S. Patent No. 5,225,347). The latter two families Derived from viroids and virusoids, ribozymes are generated during rolling circle replication. It is believed that the separation of monomers from the resulting oligomers occurs (Symons, 1989 and Hammerhead and hairpin ribozyme motifs have been used for gene therapy. It is most commonly applied for trans-cleavage of mRNA (Sullivan, 1994 Generally, ribozymes have a length of about 30 to 100 nucleotides. The delivery is similar to that of AS fragments and / or siRNA molecules.

[0121] As used herein, the term "nucleic acid" refers to DNA or RNA or modifications thereof. The nucleic acid may also be a modified version that allows correct read-through by a polymerase. and modified nucleotides that allow the nucleic acid to bind to the target polypeptide and do not alter the expression of the polypeptide encoded by the nucleic acid. The terms "nucleic acid" and "oligonucleotide" refer to a group of multiple nucleotides. As used herein, these are used interchangeably to refer to molecules that contain tides. The term refers to oligoribonucleotides as well as oligodeoxyribonucleotides. The term also refers to polynucleosides (e.g., polynucleotides minus the phosphate). Nucleic acids include any organic base containing polymers. Nucleic acid molecules include, for example, plasmids, as well as oligonucleotides. The acid can be obtained from any source, but is preferably synthetic (e.g., oligonucleotide synthesis). generated by

[0122] The polynucleotides used in accordance with the embodiments disclosed herein may be used to improve therapeutic Nucleotide modifications or analogs can be introduced to have therapeutic properties. The therapeutic properties of the polynucleotide can be improved by introducing the polynucleotide. These include increased resistance to cleavage and / or increased ability to permeate cell membranes. In this case, nuclease resistance may be achieved by incorporating AS polynucleotides as needed for the method of use and delivery. that do not interfere with the biological activity of the nucleotides, siRNA, cDNA and / or ribozymes. provided by any method known in the art (Iyer et al., 1999). 90;Eckstein,1985;SpitzerandEckstein,1988 ; Woolf et al., 1990; Shaw et al., 1991). Nucle Modifications that can be made to oligonucleotides to enhance their ATPase resistance include phosphate Modifications of the phosphorus or oxygen heteroatoms of the backbone are included. These include methylphosphonates, This includes the preparation of phosphorothioates, phosphorodithioates, and morpholino oligomers. In one embodiment, it is a link between the 4 to 6 3' terminal nucleotide bases. Alternatively, the phosphorothioate bond may be provided. The nucleotide bases are linked by a nucleotide bond, which retains biological activity but Other modifications known in the art may be used if the stability to enzymes is substantially increased. Decorations can be used.

[0123] All analogs or modifications of polynucleotides are intended to be construed as meaning that the analogs or modifications are not constitutive of the polynucleotide. The embodiments disclosed herein, provided that they do not substantially affect the function of the octide. Nucleotides may be used in combination with naturally occurring or synthetic modified bases. Naturally occurring bases include adenine, guanine, cytosine, thymine, and thiamine. Modified nucleotide bases include inosine, xanthine, Hypoxanthine, 2-aminoadenine, 6-methyl, 2-propyl and other alkyl Denine, 5-halouracil, 5-halocytosine, 6-azacytosine and 6-azathymine , pseudouracil, 4-thiuracil, 8-haloadenine, 8-aminoadenine, 8-thi ol adenine, 8-thiol alkyl adenine, 8-hydroxyl adenine and other 8-substituted adenines, 8-haloguanines, 8-aminoguanines, 8-thiolguanines, 8 -thioalkylguanine, 8-hydroxylguanine and other substituted guanines, other aza and deazaadenine, other aza and deazaguanine, 5-trifluoromethyluracil These include 5-trifluorocytosine and 5-trifluorocytosine.

[0124] Furthermore, the structure of nucleotides is radically altered, making them more suitable as therapeutic or experimental reagents. Nucleotide analogs can be prepared using the polynucleotides listed above. Examples of nucleotide analogs are , the deoxyribose (or ribose) phosphate backbone in DNA (or RNA is a peptide) Peptide nucleic acids (PNAs) are peptide nucleic acids in which the backbone is replaced by a polyamide backbone similar to that found in PNA analogs are resistant to enzymatic degradation and are useful in vivo and in vivo. It has been shown to increase the life span in vitro. Furthermore, PNAs are more readily adaptable to complementary DNA molecules than DNA molecules. It has been shown that PNA binds strongly to the DNA sequence. This observation is due to the electrical potential between the PNA strand and the DNA strand. Other modifications that can be made to oligonucleotides include poly( mer backbone, cyclic backbone, or acyclic backbone, as well as LNA ("locked nucleoside"). ic acid).

[0125] The embodiments disclosed herein also provide for the following steps for Cdc42-specific inhibitory nucleic acids: The degree of homology or identity of the nucleic acid (e.g., siRNA) may be: 35%, 36% , 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46% ,47%,48%,49%,50%,51%,52%,53%,54%,55%,56% ,57%,58%,59%,60%,61%,62%,63%,64%,65%,66% ,67%,68%,69%,70%,71%,72%,73%,74%,75%,76% ,77%,78%,79%,80%,81%,82%,83%,84%,85%,86% ,87%,88%,89%,90%,91%,92%,93%,94%,95%,96% , 97%, 98%, 99%, or a range bounded by any two of the aforementioned percentages Candidate Cdc42-specific inhibitory nucleic acids with 35% or more homology or identity are identified by the methods of the art. The proteins can be identified by methods known in the art and then subjected to functional assays, e.g. These can be determined using the assays described herein and known in the art. This can be done.

[0126] The term "homology" refers to the degree of similarity between two polynucleotide or two polypeptide moieties. The correspondence between sequences from one portion to another is known in the art. Homology can be determined by known techniques. For example, homology can be determined by aligning sequence information. By using readily available computer programs, Determined by direct comparison of sequence information between polynucleotide or polypeptide molecules Alternatively, the homology can be determined under conditions that result in the formation of a stable duplex between the homologous regions. hybridization of polynucleotides with a single-strand specific nuclease and sizing of the digested fragments. At least about 80%, preferably at least about 90%, of the nucleotides or amino acids Most preferably, at least about 95% of the molecules are defined using the above method. Two DNA or two polypeptide sequences are considered "identical" to each other if they match over their entire length. "Qualitatively homologous."

[0127] Preparation of peptides and polypeptides In some embodiments, the Cdc42-specific inhibitor is a polypeptide (e.g., The polypeptide can be a dominant-negative peptide, antibody, or affibody. , for example, via several methods known in the art (e.g., synthetically or It can be produced (via recombinant methods).

[0128] The terms "polypeptide," "peptide," and "protein" are used herein to refer to Used interchangeably, this term refers to a polymer of amino acid residues. amino acid polymers in which the amino acid residues are analogs or mimetics of corresponding naturally occurring amino acids, Polypeptides also apply to naturally occurring amino acid polymers. Polypeptides can be modified by the addition of carbohydrate residues to form proteins. The terms "peptide," "peptide," and "protein" include glycoproteins, Polypeptide products can be purified using standard solid phase techniques, including non-glycoproteins. These methods include exclusive solid-phase synthesis, partial solid-phase synthesis, and biochemical synthesis. These include, but are not limited to, synthesis, fragment condensation, and classical solution synthesis. method is useful when the peptide is relatively short (e.g., 10 kDa) and / or If it cannot be produced by recombinant technology (e.g., it is not encoded by a nucleic acid sequence), Therefore, it is preferred to use a procedure involving different chemistries. are well known in the art, and John Morrow Stewart and Jan is Dillaha Young,Solid Phase Peptide Syn theses(2ndEd.,Pierce Chemical Company,19 84). The synthetic polypeptides can be optionally purified using preparative high performance liquid chromatography. It can be purified by chromatography [Creighton T. (1983 )Proteins, structures and molecular princ [S. W.H. Freeman and Co., NY], followed by amino acid sequencing. If a large amount of polypeptide is desired, B itter et al.,(1987)Methods in Enzymol.15 3:516-544, Studier et al. (1990) Methods in Enzymol.185:60-89, Brisson et al. (1984)N ature 310:511-514, Takamatsu et al. (1987) EMBOJ.6:307-311,Coruzzi et al.(1984)EMBO J.3:1671-1680 and Brogli et al.,(1984)Sc ience224:838-843, Gurley et al. (1986) Mol. Cell.Biol.6:559-565andWeissbach&Weissbac h,1988,Methods for Plant Molecular Biology,A academicPress, NY, Section VIII, pp421-463, etc. It can be produced using recombinant techniques such as those described by et al.

[0129] In some embodiments, the method of producing a polypeptide or fragment thereof comprises: The polypeptide containing the cDNA of the gene is cloned into an expression vector, and the encoded polypeptide is expressed. Culturing cells containing the vector to express the polypeptide, and then These are all described, for example, in Marshak et al., “S strategies for Protein Purification and C haracterization.Alaboratory course manua l." Using methods known in the art, such as those described in CSHL Press (1996). (Furthermore, see, e.g., Bibl Hematol. 1965;23:116 5-74 Appl Microbiol.1967July;15(4):851-6 ;CanJ.Biochem.1968 May;46(5):441-4;Bioch emistry.1968 July;7(7):2574-80;ArchBioch emBiophys.1968 Sep.10;126(3):746-72;Bioc hemBiophysResCommun.1970 Feb.20;38(4):82 (See 5-30).

[0130] The expression vector may contain a promoter to control the transcription of the heterologous material, and It can be either a constitutive or an inducible promoter to allow selective transcription. Optionally, enhancers may be included as necessary to obtain the desired transcription level. The vehicle may also contain a selection gene.

[0131] Vectors can be introduced into cells or tissues by any of a variety of methods known in the art. Such methods can be implemented in a variety of ways. ecular Cloning:A Laboratory Manual,Cold Springs Harbor Laboratory,New York(1989,19 92),inAusubel et al.,Current Protocols i n Molecular Biology,John Wiley and Sons, Baltimore, Md. (1989), Vega et al., GeneTarg eting, CRCPress, Ann Arbor, Mich. (1995), Vect ors:ASurvey of Molecular Cloning Vectors and Their Uses,Butterworths,Boston Mass (1988) and Gilboa et al. (1986), and generally can be found.

[0132] Preparation of anti-Cdc42 antibody Antibodies that bind to Cdc42 or fragments derived therefrom are useful as immunizing antigens for intact Cdc42. It can be prepared using a polypeptide or a fragment containing a smaller polypeptide. For example, the N-terminus or C-terminus of Cdc42 or any other suitable domain can be used. It may be desirable to produce antibodies that specifically bind to the The polypeptides used can be derived from translated cDNA or chemically synthesized, If desired, it can be conjugated to a carrier protein. Chemically conjugated to the polypeptide Commonly used carriers include keyhole limpet hemocyanin ( KLH), thyroglobulin, bovine serum albumin (BSA), and tetanus toxoid. The coupled polypeptide is then used to immunize the animal.

[0133] Optionally, polyclonal or monoclonal antibodies may be obtained, e.g., from a human immunoglobulin (HIV)-1-associated antigen (HIV-1) antigen. The selected polypeptide or peptide binds to the matrix and is eluted therefrom. Those skilled in the art will be able to further purify the polyclonal antibodies and Various techniques common in immunology for the purification and / or concentration of monoclonal antibodies are Known (Coligan et al, Unit 9, Current Protocol ols in Immunology, Wiley Interscience, 199 4).

[0134] Methods for producing antibodies of all types, including fragments, are known in the art. (e.g., Harlow and Lane, Antibodies:ALb oratory Manual, Cold Spring Harbor Labora (See, e.g., Tory, New York (1988)). methods for preparing antibodies, determining antibody binding, isolating antibodies, obtaining monoclonal antibodies, and All immunization methods, including all necessary steps of humanization of monoclonal antibodies, are It is well known to those skilled in the art.

[0135] The antibody may be a humanized antibody or a human antibody. The antibody may be a CDR-grafted antibody. EP239,400, PCT publication WO0.91 / 09967;U S.Pat.Nos. 5,225,539; 5,530,101, and 5,585, 089, veneering or resurfacing(EP592,106;E P519,596;Padlan,Molecular Immunology 28( 4 / 5):489-498(1991);Studnicka et al.,Prot. ein Engineering 7(6):805-814(1994));Rogu ska et al., PNAS91:969-973(1994)), and cha in shuffling (US Pat. No. 5,565,332) Humanization can be performed using techniques known in the art.

[0136] By definition, a monoclonal antibody is a single antibody derived from one species (mouse, rabbit, goat, rat, human) ), and antibodies derived from two (or more) of these, such as chimeric antibodies and humanized antibodies. Antibodies derived from various species are included.

[0137] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. phage display methods using antibody libraries derived from globulin sequences, It can be made by a variety of methods known in the art. 44,887 and 4,716,111, and PCT application WO98 / 46645; WO98 / 50433, WO98 / 24893, WO98 / 16654, WO96 / 34 See also WO96 / 096, WO96 / 33735, and WO91 / 10741, which each of which is incorporated herein by reference in its entirety.

[0138] Additional information on all types of antibodies, including humanized antibodies, human antibodies, and antibody fragments Additional information can be found in WO 01 / 05998, which is incorporated herein by reference in its entirety. be absorbed.

[0139] Neutralizing antibodies may be further screened for neutralizing activity, possibly by viability assays. It can be prepared by the above method with the addition of a cap.

[0140] The embodiments disclosed herein may also be used in conjunction with, for example, Nygren PA 2008 FE As described in BS Journal 275:2668-2676, Afibo, a non-Ig binding protein developed using novel protein engineering principles Regarding the preparation and use of Di.

[0141] The polypeptides used in the embodiments disclosed herein may also exhibit their therapeutic activity. It can be modified, possibly chemically modified, to improve it. " - when referring to a polypeptide, at least one of the amino acid residues of which has undergone processing or may be produced by natural processes such as other post-translational modifications or by chemical processes known in the art. It refers to a polypeptide that has been modified by a modification technique. Among the many well-known modifications, typical Typical, but not exclusive, examples include acetylation, acylation, amidation, and ADP-ribose. glycosylation, GPI anchor formation, covalent attachment of lipids or lipid derivatives, methylation , myristylation, PEGylation, prenylation, phosphorylation, ubiquitination, or similar processes. Examples include:

[0142] Additional possible polypeptide modifications (e.g., resulting from changes in the nucleic acid sequence) include substitutions, deletions, This includes deletions and insertions.

[0143] "Conservative substitution" refers to the replacement of an amino acid of one class with an amino acid of the same class. The classes refer to the general physicochemical properties of the amino acid side chains, and are, for example, standard Da Determined by the yhoff frequency exchange matrix or the BLOSUM matrix It is defined by the high frequency of substitutions found in homologous polypeptides in nature.

[0144] "Non-conservative substitution" refers to the substitution of one class of amino acid for another class of amino acid. For example, class II residues Ala may be substituted with Asp, Asn, Glu, or Gln. and the like.

[0145] A "deletion" refers to the absence of one or more nucleotides or amino acid residues, respectively. This refers to a change in either the amino acid sequence or the structure.

[0146] An "insertion" or "addition" refers to one or more nucleotides, respectively, compared to the naturally occurring sequence. A change in the nucleotide or amino acid sequence that results in the addition of a nucleotide or amino acid residue Refers to...

[0147] A "substitution" is the replacement of one or more nucleotides or amino acids with different nucleotides or amino acids, respectively. With respect to amino acid sequences, substitutions can be conservative or non-conservative. It can be objective.

[0148] The embodiments disclosed herein also provide for the production of Cdc42-specific inhibitory polypeptides. Polypeptides that may have the following degrees of homology or identity (e.g., dominant negative Containing polypeptides or antibodies: 35%, 36%, 37%, 38%, 39%, 40% , 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% , 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% , 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70% ,71%,72%,73%,74%,75%,76%,77%,78%,79%,80% ,81%,82%,83%,84%,85%,86%,87%,88%,89%,90% , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or The range enclosed by any two of the above percentages. 35% or more homology or identity Candidate Cdc42-specific inhibitory polypeptides having the formula: can then be identified by functional assays, such as those described herein. and can be determined using assays known in the art.

[0149] Pharmaceutical Compositions and Administration Pharmaceutical compositions for the methods provided herein are also provided herein. In embodiments, the pharmaceutical composition comprises a Cdc42-specific inhibitor and a pharmaceutically acceptable carrier. Includes.

[0150] The compounds or mixtures of compounds described herein may be synthetic, naturally occurring, or otherwise. The compounds or mixtures of compounds described herein may be any combination of amino acids. It can include acids, nucleotides, carbohydrates, lipids, polysaccharides, etc. The compound or mixture of compounds is preferably a Cdc42-specific inhibitor (e.g., CAS The compounds, or mixtures of compounds described herein, may be used in a variety of ways, as will be apparent to those skilled in the art. It can be formulated into a pharmaceutical composition containing a pharmaceutically acceptable carrier and other excipients, as described above. Such compositions are useful in the treatment of, among other things, the conditions, diseases, and / or disorders described herein. For this purpose, it may further contain effective amounts of other compounds.

[0151] Some embodiments provide a pharmaceutically effective amount of an active agent or a pharmaceutically acceptable salt thereof. or esters, active agent analogs or pharmaceutically acceptable salts or esters thereof, includes the administration of combinations thereof.

[0152] The compositions and preparations described preferably contain at least 0.1% of the active agent. Of course, the percentage of the compositions and preparations may be varied and the dosage may vary. It may comprise from about 2% to 60% by weight of the compositions and preparations. The dosage ranges from approximately 2, 5, 10, or 15% of the dose weight to 30, 35, 40, 45, or 5%. Such pharmaceutically useful compositions and preparations may contain 0, 55, or 60% of the active ingredient. The amount of active compound in the formulation is such that a suitable dosage will be obtained.

[0153] The active agents can form salts, which are also within the scope of the preferred embodiments. References in the specification to compounds of active agents include references to salts thereof unless otherwise indicated. It is understood that the term "salt" as used herein refers to a salt of an inorganic and / or organic acid and and bases. a basic moiety such as, but not limited to, an amine or pyridine or imidazole ring and an acidic moiety, such as, but not limited to, a carboxylic acid, The term "salt" as used herein includes the formation of hydroxybenzoates, which can form inner salts ("inner salts"). Pharmaceutically acceptable (e.g., non-toxic, physiologically acceptable) salts are preferred, although other Salts of the formula (I) are also useful, for example, in isolation or purification steps that may be used during preparation. The salt of the active agent compound can be prepared, for example, by dissolving the active agent compound in a medium, such as a medium in which the salt precipitates. In a liquid or aqueous medium, the reaction is carried out with an equal amount of acid or base, followed by lyophilization. and

[0154] basic, such as but not limited to, an amine or pyridine or imidazole ring The active agent containing moiety can form salts with a variety of organic and inorganic acids. Acid addition salts include acetates (formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid). such as), adipates, alginates, ascorbates, aspartates, benzoates Salts, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, Camphor sulfonate, cyclopentane propionate, digluconate, dodecyl sulfate ester, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate , hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), aqueous bromide hydrobromide (formed with hydrogen bromide), hydroiodide, 2-hydroxyethanesulfonate, lactate Salts, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid) (used in food), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectin acid salts, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, Propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfuric acid salts, sulfonates (such as those described herein), tartrates, thiocyanates, toluene Examples of suitable hydroxybenzoates include benzoyl sulfonates, undecanoates, and the like.

[0155] Active agents containing an acidic moiety, such as, but not limited to, carboxylic acids, are suitable for use in a variety of organic and and inorganic bases. Exemplary base salts include ammonium salts; Alkali metal salts such as thorium, lithium, and potassium salts; calcium and magnesium alkaline earth metal salts such as sodium salts; benzathine, dicyclohexylamine, hydrabamine Organic compounds such as N,N-bis(dehydro-abietyl)ethylenediamine Salts with bases (e.g., organic amines), N-methyl-D-glucamine, N-methyl-D-glucamine These include salts with lucamide, t-butylamine, and amino acids such as arginine and lysine. The basic nitrogen-containing group is a halogenated lower alkyl (e.g., methyl, ethyl, propyl chloride). , butyl, bromide, iodide), dialkyl sulfates (e.g., dimethyl sulfate, diethyl, djibutyl aryl, diamyl) chain halides (e.g., decyl, lauryl, myristyl and stearic acid) aryl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and It can be quaternized with agents such as phenethyl bromide and phenethyl bromide.

[0156] Prodrugs and solvates of the compounds of the preferred embodiments are also contemplated herein. As used herein, the term "prodrug" refers to a drug that undergoes metabolism or undergoes chemical transformation by a chemical process to produce the active agent compound, and / or its salt and The solvates of the active agent are preferably those formed by hydrolysis. It is a Japanese product.

[0157] The active agents and their salts can exist in their tautomeric forms (e.g., As amides or imino ethers). All such tautomeric forms are preferred embodiments. Contemplated herein as part of the embodiments.

[0158] Enantiomeric forms (which may exist even without asymmetric carbons) and diastereomers Asymmetric carbon atoms, including those that can exist on any of the substituents, are also included in the present invention. All stereoisomers of the compounds of the invention are contemplated and are within the scope of the preferred embodiments. The individual stereoisomers of the compounds of certain embodiments may be, for example, substantially free of other isomers or or, for example, as a racemate or with all or other selected stereoisomers. The chiral centers of the preferred embodiment are those according to the IUPAC 1974 Recommendations. It can have the S or R configuration as defined by:

[0159] When the compounds according to the preferred embodiments are in the form of salts, they are preferably pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable salts, and the like. base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts Acid addition salts include salts of inorganic and organic acids. Representative of suitable inorganic acids: Typical examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, protic acid, Pionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, Malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, Citric acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bis Methylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citric acid, aspartic acid, sulfuric acid Thearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamine Acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfates, nitrates, phosphates, perchlorates Acid salts, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates Examples of metal salts include lithium, sodium, potassium, etc. Ammonium and magnesium salts. Ammonium and alkylated ammonium salts Examples include ammonium, methylammonium, dimethylammonium, trimethylammonium ammonium, ethylammonium, hydroxyethylammonium, diethylammonium Examples of organic bases include butylammonium and tetramethylammonium salts. Examples of the amino acids include lysine, arginine, guanidine, diethanolamine, and choline.

[0160] Pharmaceutically acceptable salts can be prepared by dissolving the active agent in ether, THF, methanol, t-butanol, In a solvent such as dioxane, isopropanol, or ethanol, 1 to 4 equivalents of hydroxyl Sodium, sodium methoxide, sodium hydride, potassium t-butoxide, hydroxide It can be prepared by reacting it with a base such as calcium hydroxide or magnesium hydroxide. Mixtures of solvents can be used. Lysine, arginine, diethanolamine Organic bases such as benzophenone, choline, guanidine and their derivatives can also be used. Alternatively, the acid addition salts may be prepared by dissolving in ethyl acetate, ether, alcohol, acetone, In solvents such as THF and dioxane, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluene ethanesulfonic acid, methanesulfonic acid, fonic acid, acetic acid, citric acid , maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid It is prepared by treating with an acid such as benzoic acid, benzenesulfonic acid, or tartaric acid. Mixtures of solvents can also be used.

[0161] The compound is available in tablets, gels, syrups, powders, aerosols, creams, lotions, and tinctures. The compositions can be formulated in a variety of forms, including solid and liquid forms such as tablets and foams.

[0162] The compositions of the preferred embodiments contain physiologically acceptable diluents, fillers, lubricants, excipients, Diluents that can be used in the composition include phosphorus, Dicalcium carbonate, calcium sulfate, lactose, cellulose, kaolin, mannitol, Sodium chloride, dry starch, powdered sugar, and hydroxypropyl methylcellulose for sustained-release tablets Examples of polymers that can be used in the composition include, but are not limited to, polyhydroxymethylcellulose (HPMC). The combination contains starch, gelatin, and sucrose, glucose, dextrose, and lactose. Fillers include, but are not limited to, sugars and the like.

[0163] Natural and synthetic gums that can be used in the composition include sodium alginate, gum ghatti, and carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone and Veegum ( Veegum). Excipients that can be used in the composition include, but are not limited to: Microcrystalline cellulose, calcium sulfate, dicalcium phosphate, starch, maize stearate These include, but are not limited to, magnesium, lactose, and sucrose. Possible stabilizers include acacia, agar, alginic acid, guar gum, and tragacanth. Amphiphilic materials such as polysaccharides, gelatin, and carbomer resins, cellulose ethers and Synthetic and semi-synthetic polymers such as, but not limited to, chitin and carboxymethyl chitin It will not be done.

[0164] Acceptable solvents include Ringer's solution, water, distilled water, and up to 50% dimethyl sulfoxide in water. Cide, propylene glycol (neat or in water), phosphate buffered saline, balanced salt solution These include, but are not limited to, water, glycol and other conventional fluids.

[0165] The dosage and regimen in which the compounds are administered will depend on the dosage form, mode of administration, the condition being treated, and The optimal therapeutic concentration will vary depending on the individual and the specifics of the patient being treated. This is best determined at that time and place through routine experimentation.

[0166] The compounds according to preferred embodiments can also be used enterally. The compound according to a preferred embodiment is administered in a dose of 100 μg to 100 mg per kg of body weight per day. Preferably, the compound according to the preferred embodiment is administered orally at a rate of The compound is approximately 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 2000, 25 0, 400, 450, or 500 μg to approximately 1, 5, 10, 25, 50, 75, 100 μg The required dose may be administered in one or more portions. For oral administration, suitable forms are, for example, tablets, gels, aerosols, pills, dragees, etc. Tablets, syrups, suspensions, emulsions, solutions, powders and granules, and the preferred method of administration The preferred method involves using a suitable form containing from 1 mg to about 500 mg of the active substance. For example, the administration method is from about 1, 2, 5, 10, 25, or 50 mg to about 100, 200, 300, or 50 mg. It consists in using suitable forms containing 00, 400, 500 mg of active substance.

[0167] The compounds according to preferred embodiments are also available as solutions for intravenous or intramuscular infusion or injection. It can be administered parenterally in the form of a liquid or suspension. Compounds based on this method are generally administered at a rate of approximately 10 μg to 10 mg per kg of body weight per day. The preferred method of administration is a solution containing about 0.01 mg to 1 mg of the active substance per ml. Preferably, the compound according to the preferred embodiment is Generally, about 10, 20, 30, 40, 50, 60, 70, per kg of body weight per day 80, 90, or 100 μg to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg The preferred dosage is about 0.01, 0.02, 0.03 per ml. , 0.04, or 0.5mg to 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0 Use a solution or suspension containing 0.7, 0.8, 0.9, or 1 mg of the active substance It consists of:

[0168] The active compounds and / or pharmaceutical compositions of the embodiments disclosed herein may be administered by a variety of routes. and is typically administered by injection or oral administration, including local or systemic administration, according to Furthermore, repeated administration can be performed as necessary.

[0169] For ex vivo administration, the active agent is added to the culture medium (appropriate for the target cells) and by any standard method that maintains cell viability, such as adding medium directly to the cells. As known in the art, any of the compounds used in this method may be administered. The medium may be aqueous and non-toxic so as not to render the cells non-viable. In vivo administration may include standard nutrients to maintain cell viability. In this case, the complex may be dissolved in, for example, a pharmaceutically acceptable carrier, such as saline and buffered saline. It can be added to physiological saline and by any of several means known in the art. Examples of administration include, for example, delivery to a tissue or organ that has target cells. By intravenous injection, including local perfusion via blood vessels, or by inhalation of aerosols, subcutaneous or Parenteral administration by intramuscular or intramuscular injection; Local administration to skin wounds and lesions, e.g., grafts and and direct transfection into bone marrow cells prepared for subsequent transplantation into a subject, and This includes direct transfection into an organ that is then transplanted into the subject. Methods of administration include oral administration, particularly when the active agent is encapsulated, or subcutaneous administration, particularly when the active agent is subcutaneous. This includes rectal administration when the drug is in the form of a drug.

[0170] Such target cells can be located within a subject or human patient, where pharmacological It is contemplated that a safe and effective amount of the active agent in a physiologically acceptable form will be administered to the patient. Generally speaking, useful pharmaceutical compositions of preferred embodiments are prepared, for example, in phosphate buffered saline. A convenient amount, e.g., about 100 mg of PEG-1000, diluted in a pharmacologically or physiologically acceptable carrier, such as saline, is It is believed to contain from 0.001% to about 10% (w / w) of the selected active compound derivative. In such circumstances, the route of administration and the final amount of material administered to a subject should be determined based on the intended use. This will be application dependent and will be apparent to those skilled in the art in view of the following examples.

[0171] The composition selected should be of low or no toxicity to cells. The toxicity of a particular compound may vary depending on the concentration of the compound used. be metabolized or eliminated by the body in a non-toxic manner It is also useful in some cases.

[0172] The examples are illustrative of the types of compounds that may be used in the methods claimed herein and are not intended to be limiting unless otherwise specified. The list is not exhaustive. Derivatives of the above compounds that meet the criteria of the claims may also have active compounds. This is preferably taken into consideration when selecting a compound.

[0173] The compound is administered so that a therapeutically effective concentration of the compound contacts affected cells of the body. In the context of the preferred embodiment, the dose administered to a subject, particularly a human, is , preferably sufficient to effect a therapeutic response in a subject over a reasonable period of time. The dosage will depend on the strength of the particular compound used and the condition of the subject, as well as the The risk of adverse side effects that may be associated with the administration of a particular compound will be determined by the subject's body weight. The presence, nature, and extent of the compound may also affect the size of the dose and the specific administration to be employed in a particular patient. Generally, the compounds of the preferred embodiments are therapeutically effective at low doses. Generally, useful dose ranges are from about 0.001 mM or less to about 100 mM or more. Preferably, the effective dose range is about 0.01, 0.05, 0.1, 0.5, 0.6, 0.7 , 0.8, or 0.9 mM to about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mM Therefore, the compounds will generally be administered in low doses.

[0174] The compound can be administered in a pharmaceutically acceptable carrier. The choice of carrier will depend on the particular compound, as well as the method for administering the composition. This will be determined in part by the particular method used to There are a wide variety of suitable formulations of pharmaceutical compositions of the embodiments.

[0175] The compounds may be administered orally, topically, parenterally, by inhalation or spray, vaginally, rectally, or sublingually. The term "administration by injection" includes intravenous, intramuscular, intravenous ... These include, but are not limited to, intranodal, intramuscular, subcutaneous and parenteral injections, as well as the use of infusion techniques. Without limitation, dermal administration can include topical or transdermal administration. The compound may be formulated in association with one or more non-toxic pharmaceutically acceptable carriers and, optionally, other active ingredients. can exist in tandem.

[0176] Compositions intended for oral use may be prepared using methods known in the art for the manufacture of pharmaceutical compositions. They can be prepared according to any suitable method. to provide the preparation, a diluent, a sweetener, a flavoring agent, a coloring agent and a preservative. The tablets may contain one or more selected drugs. The tablets may be made of any non-toxic material suitable for the manufacture of tablets. It contains an active ingredient mixed with pharmaceutically acceptable excipients. These excipients may include, for example: Inert diluents (calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, etc.), granulating and disintegrating agents (e.g., corn starch, or alginate), acid), and binders (e.g., magnesium stearate, stearic acid, or talc The tablets may be uncoated or coated by known techniques. This slows disintegration and adsorption in the gastrointestinal tract, thereby providing a longer For example, glyceryl monostearate or diglyceryl stearate may be used to provide a sustained action. A time delay material such as glyceryl stearate can be used. , can also be prepared in a solid, rapid release form.

[0177] Formulations for oral use may also be prepared in which the active ingredient is not dissolved in an inert solid diluent, such as calcium carbonate. as hard gelatin capsules mixed with cereals, calcium phosphate, or kaolin; The active ingredient is dissolved in water or an oily medium, e.g., peanut oil, liquid paraffin, or olive oil. It can also be provided as a soft gelatin capsule mixed with ointment.

[0178] Aqueous suspensions containing the active material in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients include suspending agents, e.g., sodium carboxymethylcellulose. , methylcellulose, hydroxypropyl methylcellulose, sodium alginate, poly Vinylpyrrolidone, gum tragacanth, and gum acacia, dispersing or wetting agents are naturally occurring phosphatides (e.g., lecithin), or alkylene oxides and fats. Condensation products with acids (e.g., polyoxyethylene stearate), or ethylene oxide Condensation products of ethylenediamine with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol) , or fats such as ethylene oxide and polyoxyethylene sorbitan monooleate Condensation products with partial esters derived from acids and hexitols, or ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., poly ethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, e.g. ethyl), or n-propyl p-hydroxybenzoate, one or more colorants, Contains one or more flavoring agents and one or more sweetening agents (such as sucrose or saccharin) It is possible.

[0179] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may be prepared by the addition of a dispersing agent or The active ingredient is mixed with a suitable dispersant or wetting agent, a suspending agent and one or more preservatives. Powdering or wetting agents and suspending agents are exemplified by those already mentioned above. Excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0180] The compounds may also be used in non-aqueous liquid formulations, such as vegetable oils (e.g., peanut oil, olive oil, Suspension of the active agent in a liquid paraffin or mineral oil (e.g., paraffin or peanut oil) The oil suspension may be formulated by, for example, It may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. It can be preserved.

[0181] The compounds of the preferred embodiments can also be administered transdermally using methods known to those skilled in the art. For example, a solution of the active agent in a suitable volatile solvent, optionally containing a penetration enhancer, can be used. Alternatively, the suspension may contain additional additives known to those skilled in the art, such as matrix materials and biocides. After sterilization, the resulting mixture can be formulated into a dosage form according to known procedures. Furthermore, when treated with emulsifiers and water, solutions or suspensions of the active agent can be obtained. The suspension can be formulated into a lotion or ointment.

[0182] Suitable solvents for processing transdermal delivery systems are known to those skilled in the art and include ethanol. Or lower alcohols such as isopropyl alcohol, lower ketones such as acetone, acetic acid Lower carboxylic acid esters such as ethyl, polar ethers such as tetrahydrofuran, hexa Lower hydrocarbons such as benzene, cyclohexane, and dichloromethane, chloroform, etc. Halogenated hydrocarbons such as ethylenediamine, trichlorotrifluoroethane, and trichlorofluoroethane Suitable solvents include lower alcohols, lower ketones, lower carboxylic acid esters, polar a mixture of one or more materials selected from the group consisting of carboxylic ethers, lower hydrocarbons, and halogenated hydrocarbons; may also be included.

[0183] Suitable penetration enhancers for transdermal delivery systems are known to those skilled in the art and include, for example, monohydropyridine, methylparaben ... hydroxy or polyhydroxy alcohols (ethanol, propylene glycol or benzene saturated or unsaturated C8-C18 fatty alcohols (such as lauryl alcohol), Cetyl alcohol, saturated or unsaturated C8-C18 fatty acids (stearic acid, etc.) saturated or unsaturated fatty esters (methyl, ethyl, propyl, etc.) containing up to 24 carbon atoms Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl acetate or monoglycerin esters of caproic acid, lauric acid, myristic acid, stearic acid , or palmitic acid), or saturated or unsaturated containing up to about 24 carbons in total Diesters of dicarboxylic acids (diisopropyl adipate, diisobutyl adipate, sebaceous acid diisopropyl acrylate, diisopropyl maleate, or diisopropyl fumarate) Additional penetration enhancers include phosphatidylcholinesterase inhibitors such as lecithin or cephalin. Derivatives, terpenes, amides, ketones, urea and their derivatives, and dimethyl isopropyl sorbide and ethers such as diethylene glycol monoethyl ether. Suitable penetration enhancers also include monohydroxy or polyhydroxy alcohols, saturated or Unsaturated C8-C18 fatty acid alcohols, saturated or unsaturated C8-C18 fatty acids, up to 24 saturated or unsaturated fatty esters containing up to 24 carbon atoms in total are diesters of unsaturated dicarboxylic acids, phosphatidyl derivatives, terpenes, amides, and ketones. a mixture of one or more materials selected from the group consisting of urea and its derivatives, and ethers; The composition may comprise a mixture of one or more materials selected from the following:

[0184] Suitable binder materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, and the like. Corn, polyurethane, block polymer, styrene butadiene copolymer, and natural These include natural and synthetic rubbers, cellulose ethers, derivatized polyethylene, and silica. Acid salts can also be used as matrix components. Additional additives such as viscous resins and oils can also be used. Additives can be added to increase the viscosity of the matrix.

[0185] In some embodiments, the composition may include, for example, a topical formulation. In some embodiments, the topical formulation is a non-transdermal formulation formulated to prevent penetration beyond the dermal layer. Non-transdermal formulations are known in the art and include matrix or micellar solutions. , bandages, wound dressings, aerosol sprays, foams, non-transdermal topical patches, colorants, topical This includes administration agents, etc.

[0186] The pharmaceutical compositions of preferred embodiments may also be in the form of an oil-in-water emulsion. Vegetable oil (e.g. olive oil or peanut oil) or mineral oil (e.g. liquid paraffin) Suitable emulsifiers include naturally occurring gums (e.g., akashi gum, sucralose gum, sorbitol ... gum agar or gum tragacanth), naturally occurring phosphatides (e.g., soy, tin), and esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and the partial esters of these with ethylene oxide It may be a condensation product (e.g., polyoxyethylene sorbitan monooleate). Syrups and elixirs can also contain sweeteners and flavorings. , sweeteners, such as glycerol, propylene glycol, sorbitol or sucrose Such formulations may also contain thickeners, preservatives, flavorings, and coloring agents. Coloring agents may be included.

[0187] The compounds can also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions are solid at room temperature but liquid at rectal or vaginal temperature. Therefore, the drug is mixed with a suitable non-irritating excipient that melts in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene. Contains ethylene glycol.

[0188] In all use regimens disclosed herein for the active agent, daily oral administration The regimen will preferably be from about 0.01 to about 200 mg / Kg of total body weight. The daily oral dosage regimen is preferably about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2 0.5, 1, 2, 3, 4, or 5 to approximately 10, 50, 100, 110, 120, 130, It may be 140, 150, 160, 170, 180, 190, or 200 mg / Kg. Administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and infusion The daily dosage for use in the technology is preferably between 0.01 and 200 mg / Kg of total body weight. Preferably, the drug is administered by injection, including intravenous, intramuscular, subcutaneous and parenteral injections. The daily dosage for the administration of steroids, and the use of injection techniques, is preferably about 0.01, 0.0, or 100 mg of total body weight. 5, 0.1, 0.5, 1, 2, 3, 4, or 5 to approximately 10, 50, 100, 110, 12 0, 130, 140, 150, 160, 170, 180, 190, or 200 mg / K The daily vaginal administration regimen is preferably 0.01 to 200 mg / g of total body weight. The daily topical administration regimen is preferably administered between 1 and 4 times daily. The concentration for vaginal and topical administration will be 0.01 to 200 mg. The concentration required to maintain the daily dose is 0.1 to 200 mg / kg. The oral dosage regimen is preferably about 0.01, 0.05, 0.1, 0.5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 210, 220, 1, 2, 3, 4, or 5 to about 10, 50, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg / Kg. The dosage regimen will preferably be 0.01 to 10 mg / Kg of total body weight. The daily inhalation dosage regimen is preferably about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, It may be 0.5 to about 1, 2, 3, 4, 5, or 10 mg / Kg.

[0189] The particular method of administration will depend on a variety of factors, all of which are commonly encountered when administering a therapeutic agent. It will be understood by those skilled in the art that the patient's condition may be considered in a clinical setting. The specific dose level will depend on the activity of the particular compound used, the age of the patient, the weight of the patient, and the general Consider the patient's health, sex, diet, time of administration, route of administration, excretion rate, drug combinations, etc. It will also be understood that the effectiveness of the treatment will depend on a variety of factors, including the type of treatment and the severity of the condition being treated. The optimal course of treatment, i.e., the treatment modality and the duration of the treatment, should be determined. The number of daily doses of the active agent or its pharmaceutically acceptable salt is determined based on conventional therapeutic trials. It will further be appreciated by those skilled in the art that the present invention may be verified using the methods described above.

[0190] The active compounds can be incorporated into pharmaceutical compositions suitable for administration to a subject, e.g., a human. Such compositions typically comprise nucleic acid molecules, proteins, modulators, or The antibody comprises a pharmaceutically acceptable carrier.

[0191] As used herein, the term "pharmaceutically acceptable carrier" refers to a compound that is suitable for pharmaceutical administration. Compatible with any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic The present invention is intended to include agents such as steroids, anti-inflammatory agents, and absorption delaying agents for pharmaceutically active substances. The use of such media and agents is well known in the art. Except insofar as such vehicles are incompatible with the active compound, they may be used in the compositions of the preferred embodiments. Supplementary active compounds can also be incorporated into the compositions. Pharmaceutical compositions of preferred embodiments are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), Includes transdermal, non-transdermal (topical), transmucosal, and rectal administration. The solution or suspension used for administration may contain the following components: water for injection; Saline, fixed oil, polyethylene glycol, glycerin, propylene glycol or Sterile diluents such as other synthetic solvents; antibacterial agents such as benzyl alcohol and methylparaben; Antioxidants such as ascorbic acid and sodium bisulfite; Chelating agents, buffers such as acetate, citrate, and phosphate, as well as sodium chloride and dextran Agents for adjusting tonicity, such as sucrose. pH is controlled by acids such as hydrochloric acid and sodium hydroxide. Parenteral preparations are packaged in ampoules, disposable syringes, or glass or can be packaged in a plastic multi-dose vial.

[0192] In some embodiments, the active compound is delivered by implants and microencapsulation. Use a carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation containing a steroid-resistant system. It is prepared using ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, poly Use biodegradable, biocompatible polymers such as thiol esters and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. Materials provided by Alza Corporation and Nova Pharmaceutical Liposomal suspensions (containing liposomes) are also commercially available from Pharmacia, Inc. ) can also be used as a pharmaceutically acceptable carrier. These are known to those skilled in the art. It can be prepared according to the methods described in

[0193] Oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, "dosage unit form" refers to a dosage form for It refers to physically discrete units suited as single dosages of a subject, each unit containing the necessary pharmaceutical carriers and It contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the active compound. The specifications for the dosage unit forms in the preferred embodiments depend on the unique characteristics of the active compound and the particular treatment to be achieved. therapeutic effect, as well as the inherent limitations of the technology for formulating such active compounds for the treatment of individuals. is determined by and directly depends on

[0194] As used herein, the terms "effective amount" or "therapeutically effective amount" have no meaning. patient benefit, for example, cure of a chronic condition or an increase in the cure rate of such a condition, or By "drug therapy" is meant the total amount of each active ingredient of the pharmaceutical composition or method sufficient to show a reduction in a normal state. This includes both therapeutic and prophylactic treatment. Thus, the compounds may be used to treat non-diseases. Can always be used early, before early onset, or after significant progression When applied to an individual active ingredient administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to drugs administered in combination or sequentially. A combination of active ingredients that produces a therapeutic effect, whether administered separately or simultaneously. Refers to the combined amount.

[0195] In practicing the methods of treatment or use of the preferred embodiments, a therapeutically effective amount of 1, 2, or or a further preferred embodiment of an active agent is administered to the subject. may be administered alone or in combination with other known therapies according to the methods of preferred embodiments. When co-administered with one or more other therapies, preferred embodiments The active agents can be administered simultaneously with other treatments or sequentially. If so, your doctor may administer the active agents of the preferred embodiments in combination with other therapies. The appropriate order will be determined.

[0196] Generally, a therapeutically effective amount of an active agent (i.e., an effective dose) is about 0.001 to 5000 m g / kg body weight, more preferably about 0.01 to 1000 mg / kg body weight, more preferably about 0.01 to 500 mg / kg body weight, more preferably about 0.01 to 250 mg / kg body weight, More preferably, about 0.01 to 100 mg / kg body weight, more preferably about 0.001 to 60 mg / kg body weight, more preferably about 0.01 to 25 mg / kg body weight, more preferably about 0 .1 to 20 mg / kg body weight, even more preferably about 1 to 10 mg / kg, 2 to 9 mg / kg, 3–8 mg / kg, 4–7 mg / kg, or 5–6 mg / kg body weight .

[0197] The skilled craftsman will take into account the severity of the disease or disorder, previous treatment, the subject's general health and / or or certain factors, including but not limited to age, and other medical conditions present. It will be appreciated that the various factors that influence the dosage required to effectively treat a patient may influence the dosage required to effectively treat a patient. Furthermore, treatment of a subject with a therapeutically effective amount can include a single treatment, or preferably, In a preferred embodiment, the subject receives a dose of about 0.1 to 20 mg / kg body weight. Once a week for about 1 to 10 weeks, preferably 2 to 8 weeks, more preferably about 3 to 8 weeks. The treatment is preferably for about 7 weeks, and even more preferably for about 4, 5, or 6 weeks. It will also be understood that the effective amount may increase or decrease over the course of a particular treatment. , may arise from and be evident from the results of the diagnostic assays described herein.

[0198] A preferred embodiment is directed to one or more agonists that modulate the expression or activity of Cdc42 GTPase. The agent may be, for example, a small molecule. For example, such a small molecule These include peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotides, and Nucleotide analogues, nucleotides, nucleotide analogues, organic or inorganic compounds (i.e. (i.e., heteroorganic and organometallic compounds) having a molecular weight of less than about 10,000 grams / mole organic or inorganic compounds with a molecular weight of less than about 5,000 grams per mole, and those with a molecular weight of about 1,0 Organic or inorganic compounds with a molecular weight of less than 0.00 grams per mole, less than about 500 grams per 1000g of cereals containing ... This includes, but is not limited to, forms that are acceptable.

[0199] In one embodiment, the additional agent is a compound described in U.S. Pat. Nos. 6,649,638, 5,420, No. 245, No. 5,574,025, No. 5,523,430, No. 5,602,0 No. 98, No. 5,631,401, No. 5,705,686, No. 5,238,92 2, 5,470,832 and 6,191,147. and other prenylation inhibitors, all of which are incorporated herein by reference in their entireties. It can be enjoyed.

[0200] In another embodiment, the additional agent is a compound described in U.S. Pat. No. 6,572,850, U.S. Pat. No. 58,783, No. 6,423,751, No. 6,387,926, No. 6,24 No. 2,433, same as No. 6,191,147, same as No. 6,166,067, same as No. 6,156 ,746, same as No. 6,083,979, same as No. 6,011,029, same as No. 5,929, No. 077, same as No. 5,928,924, same as No. 5,843,941, same as No. 5,786,1 No. 93, same as No. 5,629,302, same as No. 5,618,964, same as No. 5,574,02 No. 5, same as No. 5,567,841, same as No. 5,523,430, same as No. 5,510,510 No., same as No. 5,470,832, same as No. 5,447,922, same as No. 6,596,735 、Same as No. 6,586,461、Same as No. 6,586,447、Same as No. 6,579,887、 Same as No. 6,576,639, Same as No. 6,545,020, Same as No. 6,539,309, Same as No. 6,535,820, same as No. 6,528,523, same as No. 6,511,800, same as No. 6 ,500,841, same as No. 6,495,564, same as No. 6,492,381, same as No. 6,4 No. 58,935, same as No. 6,451,812, same as No. 6,441,017, same as No. 6,44 No. 0,989, same as No. 6,440,974, same as No. 6,432,959, 6,426,3 No. 52, same as No. 6,410,541, same as No. 6,403,581, same as No. 6,399,61 No. 5, same as No. 6,387,948, same as No. 6,387,905, same as No. 6,387,903 No., same as No. 6,376,496, same as No. 6,372,747, same as No. 6,362,188 、Same as No. 6,358,968、Same as No. 6,329,376、Same as No. 6,316,462、 Same as No. 6,294,552, Same as No. 6,277,854, Same as No. 6,268,394, Same as No. 6,265,382, same as No. 6,262,110, same as No. 6,258,824, same as No. No. 6,248,756, same as No. 6,242,458, same as No. 6,239,140, ​​same as No. 6 ,228,865, 6,228,856, 6,225,322, 6, No. 218,401, No. 6,214,828, No. 6,214,827, No. 6,2 Farnesyl protein trans- formation as described in US Pat. Nos. 11,193 and 6,194,438 FPTase, prenylprotein transferase or geranyl and one or more inhibitors of geranyl protein transferase, which are described by reference. No. 6,239,999, filed Dec. 1, 2003, and is specifically incorporated herein in its entirety.

[0201] "Farnesyl protein transferase inhibitors" or "FPT inhibitors" or "FTI" as used herein refers to (i) a compound that potently inhibits FPT (but generally does not inhibit geranyl) (ii) the intracellular function of ras, but not geranyl protein transferase I FPT is defined as a compound that blocks the carboxylation of Ras proteins. It catalyzes the addition of an isoprenyl lipid moiety to a cysteine ​​residue located near the oxy terminus. This is a post-translational processing pathway essential for both Ras membrane binding and Ras-induced oncogenic transformation. This is the first step in the pathway to develop new drugs, including various peptidomimetic inhibitors and other small molecule inhibitors. Many FPT inhibitors have been reported.

[0202] Farnesyltransferase inhibitors are analogs of farnesyl diphosphate and Protein substrates for renesyltransferases generally fall into two classes: Farnesyltransferase inhibitors are disclosed in U.S. Pat. No. 5,756,528, U.S. Pat. No. 5,141,851, U.S. Pat. No. 5,817,678, U.S. Pat. No. 5,830,86 No. 8, U.S. Pat. No. 5,834,434, and U.S. Pat. No. 5,773,455 all of which are incorporated herein by reference in their entireties. It has been shown to be effective in inhibiting the transfer of the Sil moiety to Ras-related proteins Among the farnesyltransferase inhibitors is L-739,749 (CAAX sequence), L-744,832 (peptidomimetic analog of CAAX sequence) analogue), SCH, 44342 (1-(4-pyridylacetyl)-4-(8-chloro-5 ,6 dihydro-IIH benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl (decane)piperidine), BZA-5B (benzodiazepine peptidomimetic), FTI-27 6 (CAAX peptidomimetic), and B1086 (CAAX peptidomimetic) The administration of farnesyltransferase inhibitors (FTIs) is known to those skilled in the art. This is achieved by standard methods known to those skilled in the art, most preferably by administration of tablets containing FTIs. It is expected that the daily dose will be in the range of approximately 0.1 mg / kg body weight to approximately 20 mg / kg body weight. can be.

[0203] In another embodiment, the additional agent is a compound as described in U.S. Pat. No. 5,470,832 (Gibbs & G As described by Raham, geranylgeranyl protein transferase (GGT), which is incorporated herein by reference in its entirety. These compounds are effective in treating individuals at doses of 0.5 mg / kg body weight to approximately 20 mg / kg body weight. Alternatively, a farnesyltransferase (FT) inhibitor and and / or one or more inhibitors containing a geranylgeranyltransferase (GGT) inhibitor A soprenylation inhibitor is administered to the patient.

[0204] In another embodiment, the additional agent is Clostridium difficile and Clostridium It contains one or more toxins, such as toxins A and B from Um Solderi lethal toxin (LT). Rho is then activated by the enzyme C3, a botulinum toxin, and the staphylococcal toxin EDIN. It can inhibit Rac1 and Rac2 when specifically ADP-ribosylated ( Narumiya, S. and Morii, S., Cell Signal, 5, 9-19. ,1993;Sekine,A. et al.,J.Biol.Chem.,264, 8602-8605, 1989, all of which are incorporated herein by reference in their entireties. (It is included).

[0205] The proper dose of a small molecule agent can be determined by many skilled physicians, veterinarians, or researchers in their laboratories. It is understood that the dosage of a small molecule will depend on, for example, the subject or site being treated. Depending on the sample identity, size, and condition of the subject or the sample being processed , further, depending on the route by which the composition is administered, if applicable, and the practitioner's Depends on the desired effect of the small molecule on the nucleic acid or polypeptide. is expressed in milligrams or micrograms per kilogram of subject or sample weight amounts of small molecules (e.g., from about 1 microgram per kilogram to about 500 micrograms per kilogram) Approximately 100 micrograms per milligram / kilogram to approximately 5 milligrams per kilogram or about 1 microgram per kilogram to about 50 micrograms per kilogram Furthermore, the appropriate dose of a small molecule may be determined by the small molecule's It will be understood that such appropriate doses will depend on the potency of the molecule. The polypeptide or nucleic acid of the preferred embodiment can be determined using an assay. One or more of these small molecules can be administered to a subject (e.g., a human) to modulate expression or activity. When administering, a doctor, veterinarian, or researcher may, for example, prescribe a relatively low dose initially, and then After this, the dose can be increased until an appropriate response is achieved. The dose level will depend on the activity of the particular compound used, age, weight, general health, sex, and and the subject's diet, time of administration, route of administration, excretion rate, any drug combination, It will be understood that the extent of expression or activity to be regulated will depend on various factors, such as the type of gene that is being regulated and the extent of expression or activity to be regulated. .

[0206] Suitable dosage ranges of the active compounds may vary depending on these considerations, but generally will be The compound is administered in the range of about 0.1 μg / kg to 5 mg / kg body weight, preferably in the range is about 1 μg / kg to 300 μg / kg body weight, more preferably about 10 μg / kg to 100 μg / kg body weight. Therefore, for a typical 70 kg subject, the dose range is The range is about 0.7 μg to 350 mg, preferably about 700 μg to 21 mg, and most preferably about When the compound is administered orally or transdermally, for example, The dose may be higher compared to intravenous administration. The compound may be administered as a single bolus dose. as doses over time, such as intravenously or transdermally, or as multiple doses It can be administered at .

[0207] The amount of active compound administered can vary according to the discretion of one skilled in the art. The amount of active compound administered to a subject is within the ranges described herein. The amount administered will vary on a clinician-determined basis.

[0208] Rejuvenation of blood progenitor cells, skin epithelial progenitor cells or intestinal epithelial progenitor cells, or active compounds The dosage regimen for weight management due to the injury depends on the type of injury, age, weight, sex, individual medical condition, and condition. The dosage regimen is based on various factors, including the severity of the condition, the route of administration, and the particular compound used. Therefore, dosing regimens can vary widely, but should be administered by physicians using standard methods. It can be routinely determined at approximately 0.1 ng / kg to 10 mg / kg body weight. Dosage levels of the active compounds are useful for all of the methods of use disclosed herein.

[0209] Treatment regimens also depend on the type of injury, age, weight, sex, individual medical condition, severity of condition, and dosage. It depends on the condition being treated, based on a variety of factors, including the route of administration and the specific compound used. It exists.

[0210] In a preferred embodiment, the active compound is administered subcutaneously. The dosage is preferably selected from the group consisting of blood progenitor cells, skin epithelial progenitor cells, and intestinal epithelial progenitor cells. Approximately 0.1 ng / kg to approximately 10 mg / kg twice daily for a period of time sufficient to increase This dosing regimen maximizes the therapeutic benefits of treatment while minimizing the amount of drug required. Such applications have costs and possible harmful side effects. Minimize.

[0211] For subcutaneous administration, the active ingredient may be present in an amount of 0.0001% to 10% w / w, e.g., 1% by weight of the formulation. It can comprise 10% w / w to 2% w / w, but is not preferred. Preferably, it is 5% w / w or less of the formulation, more preferably 0.1% to 1%. In embodiments, subcutaneous administration of about 1 to 1000 μg / kg / day of an active compound is effective in treating cancer ( For example, it is started between one week before and one week after the administration of a chemotherapy agent.

[0212] In all of these embodiments, the compound may be administered prior to, concurrently with, or in combination with any other therapeutic exposure. The administration can be made at or after the start of the treatment.

[0213] The active compounds include conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The dosage unit formulation may be administered by any suitable route, including oral, parenteral, inhalation spray, rectal, or topical administration. The term parenteral as used herein includes subcutaneous administration. , intravenous, intra-arterial, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, injection techniques, or In some embodiments, the active compound is administered intraperitoneally or intraperitoneally. It is administered as a depot containing a biocompatible matrix formulated for continuous delivery. In some embodiments, the depot is formulated to degrade over time, thereby allowing for continuous In some embodiments, the depot releases the drug in a continuous or near-continuous manner. for drug release ranging from about 1 day to about 1, 2, 3, 4, 5, 6 months or more. In some embodiments, the depot is an injectable depot for local administration. In some embodiments, the injectable depot can be subcutaneous, intravenous, intra-arterial, Intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, injection technique or intraperitoneal subcutaneous, intravenous Intra-arterial, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, injection techniques or intraperitoneal injection In some embodiments, the injectable depot is formulated for injection into the intestinal stroma. Formulated for local injection at or near the site of the injury.

[0214] The active compound may be administered in solid form (including granules, powders or suppositories) or in liquid form (e.g., solutions). These compounds can be composed of various Suitable solutions for use in accordance with the preferred embodiment include The bacteria must be capable of dissolving sufficient amounts of the peptide and be non-toxic for the proposed use. Although the compounds disclosed herein are very stable, they are easily hydrolyzed by strong acids and bases. These compounds are soluble in organic solvents and aqueous solutions with a pH of 5-8.

[0215] The active compounds may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain preservatives, Conventional adjuvants such as stabilizing agents, wetting agents, emulsifying agents, buffers, and the like may be included.

[0216] For administration, the active compound is ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. These compounds are combined with lactose, sucrose, starch powder, and Cellulose ester of acetic acid, stearic acid, talc, magnesium stearate, oxide Magnesium, sodium and calcium salts of phosphates and sulfates, acacia, gelatin , sodium alginate, polyvinylpyrrolidine, and / or polyvinyl alcohol and can be tableted or encapsulated for conventional administration. Alternatively, the compounds disclosed herein can be administered in saline, water, polyethylene glycol, or the like. propylene glycol, carboxymethyl cellulose colloidal solution, ethanol, colloid oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and / or various buffers Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may be glyceryl monostearate or glyceryl distearate. time delay material such as styrene alone or with wax, or other materials known in the art. It can include.

[0217] In some embodiments, the pharmaceutical composition comprises a GTP-bound C in senescent progenitor cells. GTP-bound Cdc42 levels in non-senescent progenitor cells with near-normal Cdc42 levels Cdc42-specific inhibitors were administered at doses sufficient to reduce the risk of In some embodiments, the pharmaceutical composition comprises hematopoietic stem and progenitor cells from bone marrow. The Cdc42-specific antibody was formulated in a dosage less than sufficient to mobilize the antibody into the peripheral blood. Contains inhibitors.

[0218] Additional Doses and Regimen Some details regarding the administration of Cdc422-specific inhibitors are provided above. Additional information regarding administration and treatment regimens is provided herein.

[0219] In some embodiments, only a single administration of a Cdc42-specific inhibitor is required to treat a subject. As explained above, this is a function of age, health, and Cdc42 This can be determined by the intrinsic properties of the subject, such as activity. and the subject requires multiple administrations of a Cdc42-specific inhibitor to achieve the desired therapeutic outcome. Thus, in some embodiments, a Cdc42-specific inhibitor may be administered to the subject. In other embodiments, the Cdc42-specific inhibitor is administered twice or more times. The Cdc42-specific inhibitor can be administered as frequently as necessary to achieve a therapeutic effect, e.g. For example, in some embodiments, administration may be 1, 2, 3, 4, 5, 6, 7, 8 or more times. 10 times, 9 times, 10 times, 1-10 times, 1-9 times, 1-8 times, 1-7 times, 1-6 times, 1-5 times, 1-4 times, 1-3 times, 2-10 times, 2-9 times, 2-8 times, 2-7 times, 2-6 times, 2-5 times , 2-4 times, 2-3 times, 3-10 times, 3-9 times, 3-8 times, 3-7 times, 3-6 times, 3-5 times times, 3-4 times, 4-10 times, 4-9 times, 4-8 times, 4-7 times, 4-6 times, 4-5 times, 5- 10 times, 5-9 times, 5-8 times, 5-7 times, 5-6 times, 6-10 times, 6-9 times, 6-8 times, 6~7 times, 7~10 times, 7~9 times, 7~8 times, 8~10 times, 8~9 times, 9~10 times, above administration times (e.g., about 3 times or about 1-3 times), or at least The administration times mentioned above (e.g., at least 3 times, at least about 3 times, or at least about 1 to 3 times) (3 times)

[0220] If two or more doses of a Cdc42-specific inhibitor are given to a subject, each dose is administered to the same Cd Cdc42-specific inhibitors, or the administration can be a different Cdc42-specific inhibitor. For example, samples from subjects may be taken and screened to identify the best possible outcome at a given dose. Cdc42-specific inhibitors can be determined (e.g., subjects can be monitored for Cdc42-specific inhibitors as treatment progresses). Cdc42 specific inhibitors may be more responsive to different Cdc42 specific inhibitors. The dose of the allotropic inhibitor may be adjusted over the course of treatment, so that the subject receives a dose that is in accordance with the course of treatment. receiving the same or different doses of the same or different Cdc42-specific inhibitors during Thus, in some embodiments, principles of personalized medicine are utilized to administer a dose to a subject. The Cdc42-specific inhibitor to be administered is determined.

[0221] The administration of a Cdc42-specific inhibitor to a subject in need of treatment is carried out as a regimen. In some embodiments, the administration may be for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or more. 7th, 8th, 10th, 11th, 12th, 13th, 14th, or any of the aforementioned days A range enclosed in brackets (e.g., 1-5 days or 3-7 days), or approximately any of the aforementioned days ( as a daily regimen (e.g., about 2 days, about 1-5 days, or about 3-7 days) In some embodiments, administration occurs as a regimen of non-consecutive days. In some embodiments, the administration occurs on non-consecutive days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 8 days. Sun, 8th, 10th, 11th, 12th, 13th, 14th, 1 week, 2 weeks, 3 weeks, 1 month , 2 months, 3 months, 6 months, 9 months, 1 year, 5 years, 10 years, remaining life expectancy of the subject, or before A range enclosed by or about any of the days, weeks, or months mentioned above This will be carried out during one of the following periods:

[0222] Subjects may receive multiple doses or even multiple dosing regimens as outlined above. Thus, in some embodiments, a daily regimen or a non-daily regimen may be required. Typical daily regimens are daily, weekly, monthly, every 6 months, every 9 months, every 12 months, and every 2 years. every five years, or for any of the aforementioned periods (e.g., daily to weekly, or monthly to 12-monthly), or is during one of the aforementioned periods (e.g., approximately daily to weekly, or approximately monthly to every 12 months) It is repeated.

[0223] In some embodiments, the Cdc42 activity of the subject is determined by the administration of a Cdc42-specific inhibitor. The activity may be determined before the first administration or before any subsequent administrations (e.g., activity may be determined before the first administration). Determined but not before the second dose, or before the first dose and before the second dose or before the first administration but not before the second administration, or after the third administration In some embodiments, the activity is determined before each administration of a Cdc42-specific inhibitor. determining the subject's Cdc42 activity before (e.g., before the first administration and after the second administration) Determining activity before the first dose and before the second dose and before the third dose It may be beneficial for physicians to determine the Cdc42 activity of a subject (e.g., determining the activity before administering the drug). Use the information gleaned from determining the patient's risk to prepare a patient-specific regimen or Therefore, in some embodiments, it may be beneficial to provide a In one embodiment, the regimen or administration of a Cdc42-specific inhibitor inhibits Cdc42 activity in the subject. or the administration is repeated.

[0224] To determine the appropriate regimen or administration of Cdc42-specific inhibitors, we investigated Cdc42 activity. In some embodiments, a threshold for Cdc42 specific inhibition can be used. The regimen or administration of the agent may be such that Cdc42 activity in the subject is determined to be a Cdc42-specific 1%, 2%, 3%, 4%, or 5% of Cdc42 activity in subjects before first administration of a selective inhibitor 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 1 6%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 2 6%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 6 0%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105% , 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145% , 150%, 160%, 170%, 180%, 190%, or 200%, approximately Any of the percentages, or a range bounded by any of the aforementioned percentages ( For example, about 1% to 30%, about 5% to 25%, about 5% to 20%, about 5% to 15%, or 1 %~30%, 5%~25%, 5%~20%, 5%~15%, 1%~100%, 1%~9 0%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% ~30%, 1%~20%, 1%~10%, 10%~100%, 10%~90%, 10%~ 80%, 10%~70%, 10%~70%, 10%~60%, 10%~50%, 10%~ 40%, 10%~30%, 10%~20%, 20%~100%, 20%~90%, 20% ~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20% ~30%, 30%~100%, 30%~90%, 30%~80%, 30%~70%, 30 %~60%, 30%~50%, 30%~40%, 40%~100%, 40%~90%, 4 0%~80%, 40%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~90%, 50%~80%, 50%~70%, 50%~60%, 60%~100% , 60%~90%, 60%~80%, 60%~70%, 70%~100%, 70%~90 %, 70%~80%, 80%~100%, 80%~90%, 90%~100%, approx. Percentages for any of the aforementioned ranges (e.g., about 10% to 70%, about 30% to 60%, or about 50% to 70%), or about 25%, about 30%, about 40%, about 50%, Approximately 55%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 100%, approximately 105%, approximately 11 Repeat if 0%, about 115%, about 120%, or about 125%.

[0225] To determine the regimen or administration of a Cdc42-specific inhibitor, In addition to, or as an alternative to, relying on, the regimen or administration can be determined by the ratio of Cdc42-GTP to total Cdc42 levels in a subject In some embodiments, the total Cdc42 level of Cdc42-GTP in the subject The ratios to the baseline values ​​were 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, and 1 .7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2 .7, 2.8, 2.9, or 3.0, and approximately 1.0, 1.1, 1.2, 1.3, or 1 before administration .4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2 .4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0, 1.0, 1.0 before administration. 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2. 1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 greater than, or approximately 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1 before administration. 7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2. In some embodiments, the β-glucan concentration is greater than 1.7, 2.8, 2.9, or 3.0. ,2%,3%,4%,5%,6%,7%,8%,9%,10%,11%,12%,13% , 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23% , 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45% , 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%; less Both are approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12% %, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22 %, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40 %, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90 %; at least 10%~90%, 10%~80%, 10%~70%, 10%~70%, 1 0%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 2 0%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~100%, 30%~90% , 30%~80%, 30%~70%, 30%~60%, 30%~50%, 30%~40% , 40%~100%, 40%~90%, 40%~80%, 40%~70%, 40%~60 %, 40%~50%, 50%~100%, 50%~90%, 50%~80%, 50%~7 0%, 50%~60%, 60%~100%, 60%~90%, 60%~80%, 60%~ 70%, 70%~100%, 70%~90%, 70%~80%, 80%~100%, 80 % to 90%; or at least 10%, 20%, 30%, 40%, 50%, 60%, 7 0%, 80%, and 90% of subjects' blood progenitor cells were Cdc42-specific inhibitor-inhibited before administration. In some embodiments, the ratio of Cdc42-GTP to total Cdc42 levels is as described above. In this study, the relationship between Cdc42-GTP and total Cdc42 levels in blood progenitor cells of the subject was The ratio is decreased after administration of a Cdc42-specific inhibitor. The ratio of Cdc42-GTP to total Cdc42 levels in the blood progenitor cells was after administration, less than 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, or Cdc4 less than about 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 after administration of a 2-specific inhibitor In some embodiments, the total Cdc42-GTP in blood progenitor cells is The ratio to dc42 levels was at least 0.8 after administration of a Cdc42-specific inhibitor. 0.9, 1.0, 1.1, 1.2 or more, or at least about 0.8, 0.9, 1.0, 1 .1, 1.2 or higher.

[0226] Some subjects may be given a 24-hour rest period to maintain the above levels and rates of CDC42 activity. Patients may benefit from repeated administration of Cdc42-specific inhibitors throughout their lives. Other subjects will undergo a treatment regimen to maintain the above levels and ratios of CDC42 activity. Repeated administration of Cdc42-specific inhibitors may be beneficial, although some patients To maintain the above-mentioned levels and ratios of CDC42 activity, we investigated the effect of Cdc42-specific inhibitors. Therefore, in some embodiments, continuous exposure to The subject is to receive a CDC42 inhibitor for the remainder of the subject's life to maintain the above levels and ratios of CDC42 activity. In another embodiment, the subject is administered a Cdc42-specific inhibitor over a period of time. To maintain the above levels and ratios of Cdc42 activity, Cdc42 activity should be monitored throughout the course of the treatment regimen. In yet another embodiment, the subject is administered a specific inhibitor at the end of the course of the treatment regimen. Instead, exposure to the Cdc42-specific inhibitor is discontinued. The subject is discontinued from exposure to the Cdc42-specific inhibitor, and the Cdc42-specific inhibitor in said subject is determined to be The selective inhibitor-mediated changes are maintained after exposure is discontinued.

[0227] In some embodiments, the subject is evaluated based on one or more of the subject's circulating cytokine levels. and selected for treatment with a Cdc42-specific inhibitor. and one or more of the subject's circulating cytokine levels are increased after the first administration of a Cdc42-specific inhibitor. or before any subsequent administration (e.g., activity is determined before the first administration). but not determined before the second administration, or activity before the first administration and before the second administration or determining activity before the first administration but not before the second administration, but before the third administration. In some embodiments, the circulating cytokine activity is determined prior to administration of the compound. The levels of interferon gamma, interleukin 1 alpha, interleukin 1 beta, and or interleukin 9, as well as any combination thereof. In this condition, one or more of the subject's circulating cytokine levels are used to administer a Cdc42-specific inhibitor. In some embodiments, the subject is selected for treatment with a Cdc42-specific inhibitor. determining one or more of the subject's circulating cytokine levels prior to each administration of determining circulating cytokine levels before administration of the first and before administration of the second or first Determine circulating cytokine levels before dose and before second and third dose It may be beneficial for a physician to determine the levels of one or more circulating cytokines in a subject. Use the information gathered from determining the patient's risk to prepare a patient-specific regimen or It may be beneficial to provide patient-specific treatment. Therefore, the regimen or administration of a Cdc42-specific inhibitor may induce one or more circulating cycles in a subject. The dose is determined based on the steroid level, or the administration is repeated.

[0228] In some embodiments, the subject's circulating inflammatory cytokine levels are Determined before the first dose of a dc42-specific inhibitor or before any subsequent doses (e.g., , determining activity before the first administration but not before the second administration, or The activity may be determined before administration and before the second administration, or after the first administration but not before the second administration. (The activity is determined before the first administration, but before the third administration). In this state, the circulating inflammatory cytokine levels determined are interferon gamma, interferon interleukin 1α, or interleukin 1β, and any combination thereof. In some embodiments, one or more of the subject's circulating inflammatory cytokine levels are used. In some embodiments, the subject is selected for treatment with a Cdc42-specific inhibitor. 1. Measure one of the circulating inflammatory cytokine levels of the subject before each administration of the Cdc42-specific inhibitor Determine the above (e.g., circulating inflammatory cells before the first administration and before the second administration). Determining the IL-1 levels before the first dose, the second dose, and the third dose It may be beneficial for physicians to determine circulating cytokine levels before administering the drug. utilizing information gathered from determining the levels of one or more circulating inflammatory cytokines Therefore, it may be beneficial to prepare a patient-specific regimen or provide patient-specific treatment. Thus, in some embodiments, a regimen of Cdc42-specific inhibitors Alternatively, the administration may be determined based on one or more levels of circulating inflammatory cytokines in the subject. or repeated administration.

[0229] Circulating cytokine levels or thresholds for circulating inflammatory cytokine levels are used to target treatment. To identify Cdc42-specific inhibitors or to determine the appropriate regimen or administration In some embodiments, the determined circulating cytokines in a subject can be used to One or more of the circulating inflammatory cytokine levels were significantly higher than those in the control population. 1%, 2%, 3%, 4%, and 5% of cytokine levels or circulating inflammatory cytokine levels ,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16% , 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26% , 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60% ,65%,70%,75%,80%,85%,90%,95%,100%,105%,1 10%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 1 50%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 3 00%, 350%, or approximately any of the foregoing percentages, or A range enclosed in one of the percentages (e.g., about 1% to 30%, about 5% to 25%, about 5 %~20%, about 5%~15% or 1%~30%, 5%~25%, 5%~20%, 5%~ 15%), 1% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60% , 1%~50%, 1%~40%, 1%~30%, 1%~20%, 1%~10%, 10%~ 100%, 10%~90%, 10%~80%, 10%~70%, 10%~70%, 10% ~60%, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 20% ~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20 %~50%, 20%~40%, 20%~30%, 30%~100%, 30%~90%, 3 0%~80%, 30%~70%, 30%~60%, 30%~50%, 30%~40%, 4 0%~100%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~90%, 50%~80%, 50%~70% , 50%~60%, 60%~100%, 60%~90%, 60%~80%, 60%~70 %, 70%~100%, 70%~90%, 70%~80%, 80%~100%, 80%~ 90%, 90%-100%, or any of the aforementioned percentage ranges (e.g., Approximately 10% to 70%, approximately 30% to 60%, or approximately 50% to 70%, or approximately 25%, approximately 30%, approximately 40%, approximately 50%, approximately 55%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 100%, approximately 105%, approximately 110%, approximately 115%, approximately 120%, or approximately 125% If so, the subject is selected for treatment with a Cdc42-specific inhibitor. In some embodiments, the control population is based on age. , 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 6 5, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 , 79, 80 years old, or a range bounded by one of the aforementioned ages (e.g., 18-20, 2 5~35, 50~80, 50~70, 50~60, 55~75, 55~75, 55~70 , ages equal to 55–65, 60–70, 52–71, 60–79, or 73–78 years. , or 18-20, 25-35, 50-80, 50-70, 50-60, 55-75, 55-75, 55-70, 55-65, 60-70, 52-71, 60-79, or 7 In some embodiments, the determined circulating blood sample is aged between 3 and 78 years. Cytokine levels were interferon-γ, interleukin-1α, and interleukin- 1β, or interleukin 9, as well as any combination thereof.

[0230] In some embodiments, the regimen or administration of a Cdc42-specific inhibitor is one of the circulating cytokine levels or circulating inflammatory cytokine levels determined in These are the circulating cytokine levels or circulating inflammatory cytokine levels in the control population. 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 1 35%, 140%, 145%, 150%, 160%, 170%, 180%, 190%, 2 00%, 225%, 250%, 300%, 350%, or approximately the aforementioned percentage Any of the above percentages, or a range bounded by any of the above percentages (e.g., approximately 1%) ~30%, about 5%~25%, about 5%~20%, about 5%~15% or 1%~30%, 5% ~25%, 5%~20%, 5%~15%, 1%~100%, 1%~90%, 1%~80 %, 1%~70%, 1%~60%, 1%~50%, 1%~40%, 1%~30%, 1%~ 20%, 1% to 10%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~ 30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20% ~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30% ~100%, 30%~90%, 30%~80%, 30%~70%, 30%~60%, 30 %~50%, 30%~40%, 40%~100%, 40%~90%, 40%~80%, 4 0%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~90%, 50%~80%, 50%~70%, 50%~60%, 60%~100%, 60%~90% , 60%~80%, 60%~70%, 70%~100%, 70%~90%, 70%~80 %, 80%-100%, 80%-90%, 90%-100%, approximately the aforementioned percentages Any of the ranges of the page (e.g., about 10% to 70%, about 30% to 60%, or about 50%) ~70%), or about 25%, about 30%, about 40%, about 50%, about 55%, about 60%, about 70%, approx. 80%, approx. 90%, approx. 100%, approx. 105%, approx. 110%, approx. 115%, approx. 1 In some embodiments, the control group is repeated if the control group is about 20%, or about 125%. In some embodiments, the control population is 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 1, 22, 23, 24, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54 , 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 years old, or a range bounded by one of the ages above (e.g., 18-20, 25-35, 50- 80, 50-70, 50-60, 55-75, 55-75, 55-70, 55-65, 6 Age equal to 0-70, 52-71, 60-79, or 73-78 years, or 18-2 0, 25-35, 50-80, 50-70, 50-60, 55-75, 55-75, 55 Over 70, 55-65, 60-70, 52-71, 60-79, or 73-78 years old The age is the age at which a person becomes ill.

[0231] In some embodiments, the regimen or administration of a Cdc42-specific inhibitor is one of the circulating cytokine levels or circulating inflammatory cytokine levels determined in The above is a summary of the circulatory status of a subject before the first administration of a Cdc42-specific inhibitor to the subject. 1%, 2%, 3%, 4%, and 5% of cytokine levels or circulating inflammatory cytokine levels ,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16% , 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26% , 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60% ,65%,70%,75%,80%,85%,90%,95%,100%,105%,1 10%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 1 50%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 3 00%, 350%, or approximately any of the foregoing percentages, or The range enclosed by one of the following pages (for example, about 1% to 30%, about 5% to 25%, about 5% to 2 0%, approximately 5% to 15%, or 1% to 30%, 5% to 25%, 5% to 20%, 5% to 15% ), 1%~100%, 1%~90%, 1%~80%, 1%~70%, 1%~60%, 1% ~50%, 1%~40%, 1%~30%, 1%~20%, 1%~10%, 10%~100 %, 10%~90%, 10%~80%, 10%~70%, 10%~70%, 10%~60 %, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 20%~10 0%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~5 0%, 20%~40%, 20%~30%, 30%~100%, 30%~90%, 30%~ 80%, 30%~70%, 30%~60%, 30%~50%, 30%~40%, 40%~ 100%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40% ~50%, 50%~100%, 50%~90%, 50%~80%, 50%~70%, 50 %~60%, 60%~100%, 60%~90%, 60%~80%, 60%~70%, 7 0%~100%, 70%~90%, 70%~80%, 80%~100%, 80%~90% , 90% to 100%, or approximately any of the aforementioned percentage ranges (e.g., approximately 10 %~70%, about 30%~60%, or about 50%~70%), or about 25%, about 30% , about 40%, about 50%, about 55%, about 60%, about 70%, about 80%, about 90%, about 100 %, approximately 105%, approximately 110%, approximately 115%, 120%, or approximately 125% In some embodiments, the circulating cytokine levels that are determined are Interferon gamma, interleukin 1 alpha, interleukin 1 beta, or interleukin 9, and any combination thereof.

[0232] In some embodiments, an effective amount of a Cdc42-specific inhibitor comprises administering to a subject In some embodiments, the level of circulating cytokine levels is reduced or decreased. In this study, one or more circulating cytokine levels or one or more circulating inflammatory cytokine levels were The decrease or reduction in the level is measured in the subject prior to the first administration of a Cdc42-specific inhibitor to said subject. 1% compared with circulating cytokine levels or circulating inflammatory cytokine levels in 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 300%, 350%, or approximately any of the aforementioned percentages; or a range enclosed by one of the aforementioned percentages (e.g., approximately 1% to 30%, approximately 5 %~25%, about 5%~20%, about 5%~15% or 1%~30%, 5%~25%, 5% ~20%, 5%~15%), 1%~100%, 1%~90%, 1%~80%, 1%~70 %, 1%~60%, 1%~50%, 1%~40%, 1%~30%, 1%~20%, 1%~ 10%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10% ~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10% ~20%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20 %~60%, 20%~50%, 20%~40%, 20%~30%, 30%~100%, 3 0%~90%, 30%~80%, 30%~70%, 30%~60%, 30%~50%, 3 0%~40%, 40%~100%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~90%, 50%~80% , 50%~70%, 50%~60%, 60%~100%, 60%~90%, 60%~80 %, 60%~70%, 70%~100%, 70%~90%, 70%~80%, 80%~1 00%, 80%-90%, 90%-100%, or any of the aforementioned percentage ranges (e.g., about 10% to 70%, about 30% to 60%, or about 50% to 70%) In some embodiments, the circulating cytokine levels that are determined are interleukin-γ, interleukin-1α, or interleukin-1β, and any of these It is a combination of intentions.

[0233] In some embodiments, an effective amount of a Cdc42-specific inhibitor comprises administering to a subject Reduce or decrease the levels of circulating inflammatory cytokines. In the form of one or more circulating cytokine levels or one or more circulating inflammatory cytokines A decrease or reduction in Cdc42 levels is a response to administration of an effective amount of a Cdc42-specific inhibitor. 1% compared with circulating cytokine levels or circulating inflammatory cytokine levels in control populations, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 300%, 350%, or approximately any of the aforementioned percentages; or a range enclosed by one of the aforementioned percentages (e.g., approximately 1% to 30%, approximately 5 %~25%, about 5%~20%, about 5%~15% or 1%~30%, 5%~25%, 5% ~20%, 5%~15%), 1%~100%, 1%~90%, 1%~80%, 1%~70 %, 1%~60%, 1%~50%, 1%~40%, 1%~30%, 1%~20%, 1%~ 10%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10% ~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10% ~20%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20 %~60%, 20%~50%, 20%~40%, 20%~30%, 30%~100%, 3 0%~90%, 30%~80%, 30%~70%, 30%~60%, 30%~50%, 3 0%~40%, 40%~100%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~90%, 50%~80% , 50%~70%, 50%~60%, 60%~100%, 60%~90%, 60%~80 %, 60%~70%, 70%~100%, 70%~90%, 70%~80%, 80%~1 00%, 80%-90%, 90%-100%, or any of the aforementioned percentage ranges (e.g., about 10% to 70%, about 30% to 60%, or about 50% to 70%) In some embodiments, the control population is based on age. The control group is 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 4 0, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 years old, or a range enclosed by any of the above ages ( For example, 18-20, 25-35, 50-80, 50-70, 50-60, 55-75, 55-75, 55-70, 55-65, 60-70, 52-71, 60-79, or 7 Ages equal to 3 to 78 years, or 18 to 20, 25 to 35, 50 to 80, 50 to 70, 5 0~60, 55~75, 55~75, 55~70, 55~65, 60~70, 52~71 In some embodiments, the age is greater than 60-79, or greater than 73-78 years of age. In this study, the circulating cytokine levels determined were interferon-γ, interleukin- 1α, or interleukin 1β, as well as any combination thereof.

[0234] In some embodiments, an effective amount of a Cdc42-specific inhibitor comprises administering to a subject In some embodiments, the level of circulating cytokine levels increases or increases. In the present invention, when an effective amount of a Cdc42-specific inhibitor is administered to a subject, the subject's circulating cytokine levels or circulating inflammatory cytokines before the first administration of the agent. Compared to levels of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125 %, 130%, 135%, 140%, 145%, 150%, 160%, 170%, 180 %, 190%, 200%, 225%, 250%, 300%, 350%, approximately the aforementioned percentages Any of the percentages, or a range enclosed by any of the aforementioned percentages (e.g., approximately 1% to 30%, approximately 5% to 25%, approximately 5% to 20%, approximately 5% to 15% or 1% to 30%, 5%~25%, 5%~20%, 5%~15%, 1%~100%, 1%~90%, 1%~ 80%, 1%~70%, 1%~60%, 1%~50%, 1%~40%, 1%~30%, 1 %~20%, 1%~10%, 10%~100%, 10%~90%, 10%~80%, 10 %~70%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10 %~30%, 10%~20%, 20%~100%, 20%~90%, 20%~80%, 2 0%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 3 0%~100%, 30%~90%, 30%~80%, 30%~70%, 30%~60%, 30%~50%, 30%~40%, 40%~100%, 40%~90%, 40%~80% , 40%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~90 %, 50%~80%, 50%~70%, 50%~60%, 60%~100%, 60%~9 0%, 60%~80%, 60%~70%, 70%~100%, 70%~90%, 70%~ 80%, 80%-100%, 80%-90%, 90%-100%, approximately the aforementioned percentages For any of the ranges (e.g., about 10% to 70%, about 30% to 60%, or about 50% to 70% (50% to 70%) of patients have elevated or increased levels of one or more circulating cytokines. In some embodiments, the increased or elevated circulating cytokine levels are interleukin- It is 9.

[0235] In some embodiments, upon administration of an effective amount of a Cdc42-specific inhibitor, compared with circulating cytokine levels or circulating inflammatory cytokine levels in the population. 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 1 3%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 2 3%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 4 5%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 9 5%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 13 5%, 140%, 145%, 150%, 160%, 170%, 180%, 190%, 20 0%, 225%, 250%, 300%, 350%, or approximately any of the aforementioned percentages; or a range enclosed by one of the aforementioned percentages (e.g., approximately 1% to 30%, approximately 5 %~25%, about 5%~20%, about 5%~15% or 1%~30%, 5%~25%, 5% ~20%, 5%~15%), 1%~100%, 1%~90%, 1%~80%, 1%~70 %, 1%~60%, 1%~50%, 1%~40%, 1%~30%, 1%~20%, 1%~ 10%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10% ~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10% ~20%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20 %~60%, 20%~50%, 20%~40%, 20%~30%, 30%~100%, 3 0%~90%, 30%~80%, 30%~70%, 30%~60%, 30%~50%, 3 0%~40%, 40%~100%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~90%, 50%~80% , 50%~70%, 50%~60%, 60%~100%, 60%~90%, 60%~80 %, 60%~70%, 70%~100%, 70%~90%, 70%~80%, 80%~1 00%, 80%-90%, 90%-100%, or approximately any of the aforementioned percentage ranges (e.g., about 10% to 70%, about 30% to 60%, or about 50% to 70%) There is an increase or elevation in the levels of one or more circulating cytokines. The control population is based on age. In some embodiments, the control population is 18, 19, 2 0, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 51, 52, 53 , 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 8 0 years old or a range bounded by one of the above ages (e.g., 18-20, 25-35, 50~80, 50~70, 50~60, 55~75, 55~75, 55~70, 55~6 Age equal to 5, 60-70, 52-71, 60-79, or 73-78 years, or 1 8~20, 25~35, 50~80, 50~70, 50~60, 55~75, 55~75 , 55-70, 55-65, 60-70, 52-71, 60-79, or 73-78 years old In some embodiments, the age is increased or elevated circulating serum. The cytokine level is interleukin 9.

[0236] Selecting subjects depending on a combination of one or more circulating cytokine levels; or In addition to determining the regimen or administration of Cdc42-specific inhibitors, several In some embodiments, the subject, regimen, or administration is directed to a subject that is at least one of a group of subjects, and a subject may be at least one of a group of subjects that is ... In some embodiments, the circulating cytokines are determined based on the ratio of Interferon gamma, interleukin 1 alpha, interleukin 1 beta, and / or interferon In some embodiments, the ratio is one or more of interleukin 9. Interferon-γ, interleukin-1α, or interleukin-9 In some embodiments, the circulating serum in the subject is one or more of ribozyme 1β. The ratio of cytokine levels was 1.0, 1.1, 1.2, 1.3, 1.4, 1.5 before administration. 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0, approximately 1.0, 1.1, 1.2 before administration; 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0, 1 before administration .0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2 0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or or greater than 3.0, or approximately 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, or 1.0 before administration .6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2 In some embodiments, the β-glucan concentration is greater than 0.6, 2.7, 2.8, 2.9, or 3.0. At most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12% %, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22 %, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40 %, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90 %; at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 2 1%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 3 5%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 8 5%, 90%; at least 10%~90%, 10%~80%, 10%~70%, 10%~ 70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~ 20%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20% ~60%, 20%~50%, 20%~40%, 20%~30%, 30%~100%, 30 %~90%, 30%~80%, 30%~70%, 30%~60%, 30%~50%, 30 %~40%, 40%~100%, 40%~90%, 40%~80%, 40%~70%, 4 0%~60%, 40%~50%, 50%~100%, 50%~90%, 50%~80%, 50%~70%, 50%~60%, 60%~100%, 60%~90%, 60%~80% , 60%~70%, 70%~100%, 70%~90%, 70%~80%, 80%~10 0%, 80%-90%, or at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90% of the subjects' blood progenitor cells were treated with a Cdc42-specific inhibitor. In some embodiments, the subject's circulating cytokine levels are determined to be a ratio of the aforementioned levels before and after administration. The ratio of circulating cytokine levels in blood progenitor cells in mice was significantly increased after administration of a Cdc42-specific inhibitor. In some embodiments, the circulating cytokines in the hematopoietic progenitor cells are decreased after administration. The ratio of in-levels after said administration is 1.0, 1.1, 1.2, 1.3, 1.4, or 1. less than 0.5, or approximately 1.0, 1.1, 1.2, 1.3 after administration of Cdc42-specific inhibitors In some embodiments, the IL-16 expression level in blood progenitor cells is less than 1.4 or 1.5. The ratio of circulating cytokine levels was at least 0.8 after administration of Cdc42-specific inhibitors. , 0.9, 1.0, 1.1, 1.2 or more, or at least about 0.8, 0.9, 1.0, 1.1, 1.2 or higher.

[0237] In some embodiments, the subject is assessed based on the methylation status of one or more CpG sites. CpG or CG sites are selected for treatment with Cdc42-specific inhibitors. is a sequence of bases in the 5'→3' direction, with a cytosine nucleotide followed by a guanine nucleotide. A region of DNA that continues in a linear sequence. The cytosine in the CpG dinucleotide binds to DNA methyl groups. It is methylated by transferases to form 5-methylcytosine. Methylation of cytosines can alter their expression, contributing to epigenetic and genetic In some embodiments, the methylation of cytosine within a CpG site Isolation is used to select subjects for treatment with Cdc42-specific inhibitors. Age also has a strong effect on the DNA methylation level of cytosines within CpG sites. Elephants' highly accurate biological clock (epigenetic clock or DNA methylation age) In some embodiments, an "epigenetic A "clock" is used to select targets for treatment with Cdc42-specific inhibitors.

[0238] In some embodiments, the CpG site is located in the Prima1, Hsf4, or Kcns1 gene. In some embodiments, the present invention is directed to one or more of the following: In this case, Prima1, Hsf4, Kcns1 genes and combinations thereof The methylation status of one or more of the CpG sites within the range was determined by the first Cdc42-specific inhibitor. The level may be determined before administration or before subsequent administrations (e.g., the level may be determined before the first administration). Determined before the first dose but not before the second dose, or before the first dose and before the second dose or determining the levels before the first administration but not before the second administration. (However, the level is determined before the third administration.) In some embodiments, Prima1, of one or more CpG sites in the Hsf4, Kcns1 genes, and combinations thereof Methylation status is used to select targets for treatment with Cdc42-specific inhibitors. In some embodiments, the Prima1, Hsf4, Kcns1 genes and combinations thereof The methylation status of one or more CpG sites in the 1000-kDa complex was assessed before each administration of a Cdc42-specific inhibitor. determining cytokine methylation levels (e.g., before the first administration and before the second administration) Determining levels or before the first dose and before the second dose and before the third dose It may be beneficial for physicians to In some embodiments, the Prima1, Hsf4, Kcns1 genes and combinations thereof The information gathered from determining the methylation status of one or more CpG sites in the match It is useful to prepare a patient-specific regimen or provide patient-specific treatment. Thus, in some embodiments, Prima1, Hsf4, K Methylation status of one or more CpG sites in the cns1 gene and their combinations Based on the above, the regimen or administration of the Cdc42-specific inhibitor is determined or administered. is repeated.

[0239] To identify targets for treatment or to determine appropriate regimens or doses of Cdc42-specific inhibitors. A threshold for the methylation status of one or more CpG sites can be used to determine the effect of In some embodiments, the subject Prima1, Hsf4, Kcns1 genes and The methylation status of one or more CpG sites in the α- and β-blockers and their combinations is important for determining whether a therapeutic target is a matched group. or to determine the appropriate regimen or administration of Cdc42-specific inhibitors In some embodiments, the methylation of one or more CpG sites in a subject is The methylation status of one or more CpG sites was 1%, 2%, 3%, or 4% higher than that of the control population. %, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% , 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140% , 145%, 150%, 160%, 170%, 180%, 190%, 200%, 225% , 250%, 300%, 350%, or approximately any of the aforementioned percentages; is a range enclosed by one of the above percentages (e.g., approximately 1% to 30%, approximately 5% to 25%, about 5% to 20%, about 5% to 15% or 1% to 30%, 5% to 25%, 5% to 2 0%, 5%~15%), 1%~100%, 1%~90%, 1%~80%, 1%~70%, 1%~60%, 1%~50%, 1%~40%, 1%~30%, 1%~20%, 1%~10 %, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~7 0%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 2 0%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~ 60%, 20%~50%, 20%~40%, 20%~30%, 30%~100%, 30% ~90%, 30%~80%, 30%~70%, 30%~60%, 30%~50%, 30% ~40%, 40%~100%, 40%~90%, 40%~80%, 40%~70%, 40 %~60%, 40%~50%, 50%~100%, 50%~90%, 50%~80%, 5 0%~70%, 50%~60%, 60%~100%, 60%~90%, 60%~80%, 60%~70%, 70%~100%, 70%~90%, 70%~80%, 80%~100 %, 80%-90%, 90%-100%, or any of the aforementioned percentage ranges (e.g., about 10% to 70%, about 30% to 60%, or about 50% to 70%), or about 25%, approximately 30%, approximately 40%, approximately 50%, approximately 55%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 100%, approximately 105%, approximately 110%, approximately 115%, approximately 120%, or approximately 12 If it is 5%, the subject is selected for treatment with a Cdc42-specific inhibitor. In some embodiments, the one or more CpG sites are selected from Prima1, Hsf4, Kcns In some embodiments, the referenced The methylation status is cytosine methylation. In some embodiments, the control population is age- and In some embodiments, the control population is based on , 23, 24, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 6 9, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 years old or older A range bounded by any of the ages listed above (e.g., 18-20, 25-35, 50-80, 5 0~70, 50~60, 55~75, 55~75, 55~70, 55~65, 60~70 , ages equal to 52-71, 60-79, or 73-78 years, or 18-20, 25 ~35, 50~80, 50~70, 50~60, 55~75, 55~75, 55~70, (Ages greater than 55-65, 60-70, 52-71, 60-79, or 73-78) is the age.

[0240] In some embodiments, the methylation status of one or more CpG sites in a subject is 1%, 2%, 3%, 4%, 5% or higher methylation status of one or more CpG sites compared to the control population %, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16 %, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26 %, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 300%, 350%, or approximately any of the foregoing percentages, or The range enclosed by one of the following pages (for example, about 1% to 30%, about 5% to 25%, about 5% to 2 0%, approximately 5% to 15%, or 1% to 30%, 5% to 25%, 5% to 20%, 5% to 15% ), 1%~100%, 1%~90%, 1%~80%, 1%~70%, 1%~60%, 1% ~50%, 1%~40%, 1%~30%, 1%~20%, 1%~10%, 10%~100 %, 10%~90%, 10%~80%, 10%~70%, 10%~70%, 10%~60 %, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 20%~10 0%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~5 0%, 20%~40%, 20%~30%, 30%~100%, 30%~90%, 30%~ 80%, 30%~70%, 30%~60%, 30%~50%, 30%~40%, 40%~ 100%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40% ~50%, 50%~100%, 50%~90%, 50%~80%, 50%~70%, 50 %~60%, 60%~100%, 60%~90%, 60%~80%, 60%~70%, 7 0%~100%, 70%~90%, 70%~80%, 80%~100%, 80%~90% , 90% to 100%, or approximately any of the aforementioned percentage ranges (e.g., approximately 10% ~70%, about 30%~60%, or about 50%~70%), or about 25%, about 30%, Approximately 40%, approximately 50%, approximately 55%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 100% , about 105%, about 110%, about 115%, about 120%, or about 125%, C The regimen or administration of the dc42-specific inhibitor is repeated. In some embodiments, Therefore, one or more CpG sites are located in the Prima1, Hsf4, Kcns1 genes and their In some embodiments, the methylation state is in a combination of In some embodiments, the control population is based on age. In some embodiments, the control population is 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 5 9, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 , 73, 74, 75, 76, 77, 78, 79, 80 years old, or at any of the aforementioned ages. Enclosed ranges (e.g., 18-20, 25-35, 50-80, 50-70, 50-60) , 55~75, 55~75, 55~70, 55~65, 60~70, 52~71, 60~ 79, or age equal to 73-78 years, or 18-20, 25-35, 50-80, 50~70, 50~60, 55~75, 55~75, 55~70, 55~65, 60~7 ages greater than 0, 52–71, 60–79, or 73–78 years).

[0241] In some embodiments, the methylation status of one or more CpG sites in a subject is

[0023] A method for determining the methylation of one or more CpG sites in a subject prior to first administering a Cdc42-specific inhibitor to the subject. Chilled state 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11% , 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21% , 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35% , 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% ,90%,95%,100%,105%,110%,115%,120%,125%,1 30%, 135%, 140%, 145%, 150%, 160%, 170%, 180%, 1 90%, 200%, 225%, 250%, 300%, 350%, approximately the aforementioned percentages Any of the above percentage ranges (e.g., approximately 1 % to 30%, about 5% to 25%, about 5% to 20%, about 5% to 15% or 1% to 30%, 5 %~25%, 5%~20%, 5%~15%, 1%~100%, 1%~90%, 1%~8 0%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% ~20%, 1%~10%, 10%~100%, 10%~90%, 10%~80%, 10% ~70%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10% ~30%, 10%~20%, 20%~100%, 20%~90%, 20%~80%, 20 %~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30 %~100%, 30%~90%, 30%~80%, 30%~70%, 30%~60%, 3 0%~50%, 30%~40%, 40%~100%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~90% , 50%~80%, 50%~70%, 50%~60%, 60%~100%, 60%~90 %, 60%~80%, 60%~70%, 70%~100%, 70%~90%, 70%~8 0%, 80%-100%, 80%-90%, 90%-100%, approximately the above percentages Any of the ranges of the page (e.g., about 10% to 70%, about 30% to 60%, or about 50%) ~70%), or about 25%, about 30%, about 40%, about 50%, about 55%, about 60%, about 70%, approx. 80%, approx. 90%, approx. 100%, approx. 105%, approx. 110%, approx. 115%, approx. 1 20%, or approximately 125%, the regimen or administration of Cdc42-specific inhibitors In some embodiments, one or more CpG sites are repeated. In some embodiments, the genes are Hsf4, Kcns1, and combinations thereof. In this context, the methylation state referred to is cytosine methylation.

[0242] In some embodiments, an effective amount of a Cdc42-specific inhibitor comprises administering to a subject In some embodiments, the methylation status of the CpG sites is decreased or reduced. The regimen or administration of an effective amount of a Cdc42-specific inhibitor may be used to treat one or more Cdc42-specific disorders in a subject. The methylation status of pG sites was assessed before or after the first administration of a Cdc42-specific inhibitor to the subject. Methylation of one or more CpG sites of interest before the elephant's last dose of a Cdc42-specific inhibitor Compared to the irradiated state, 1%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 2 1%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 3 5%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 8 5%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125% , 130%, 135%, 140%, 145%, 150%, 160%, 170%, 180% , 190%, 200%, 225%, 250%, 300%, 350%, approximately the aforementioned percentage Any of the percentages, or a range enclosed by any of the aforementioned percentages (e.g., Approximately 1% to 30%, approximately 5% to 25%, approximately 5% to 20%, approximately 5% to 15%, or 1% to 30% , 5%~25%, 5%~20%, 5%~15%), 1%~100%, 1%~90%, 1% ~80%, 1%~70%, 1%~60%, 1%~50%, 1%~40%, 1%~30%, 1%~20%, 1%~10%, 10%~100%, 10%~90%, 10%~80%, 1 0%~70%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 1 0%~30%, 10%~20%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~100%, 30%~90%, 30%~80%, 30%~70%, 30%~60% , 30%~50%, 30%~40%, 40%~100%, 40%~90%, 40%~80 %, 40%~70%, 40%~60%, 40%~50%, 50%~100%, 50%~9 0%, 50%~80%, 50%~70%, 50%~60%, 60%~100%, 60%~ 90%, 60%~80%, 60%~70%, 70%~100%, 70%~90%, 70% ~80%, 80%~100%, 80%~90%, 90%~100%, approximately the aforementioned percentage For any of the ranges of content (e.g., about 10% to 70%, about 30% to 60%, or or about 50% to 70%. In some embodiments, one or more CpG sites in the Prima1, Hsf4, Kcns1 genes and their combinations In some embodiments, the methylation state referred to is the methylation state of cytosine. It is transformation.

[0243] In some embodiments, the regimen or administration of an effective amount of a Cdc42-specific inhibitor compares the methylation status of one or more CpG sites in a subject with that of one or more CpG sites in a control population 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% compared to the methylation status of the site , 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% , 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% , 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% , 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120 %, 125%, 130%, 135%, 140%, 145%, 150%, 160%, 170 %, 180%, 190%, 200%, 225%, 250%, 300%, 350%, approx. Any of the percentages, or a range bounded by any of the aforementioned percentages ( For example, about 1% to 30%, about 5% to 25%, about 5% to 20%, about 5% to 15%, or 1% ~30%, 5%~25%, 5%~20%, 5%~15%, 1%~100%, 1%~90 %, 1%~80%, 1%~70%, 1%~60%, 1%~50%, 1%~40%, 1%~ 30%, 1% to 20%, 1% to 10%, 10% to 100%, 10% to 90%, 10% to 8 0%, 10% to 70%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 4 0%, 10%~30%, 10%~20%, 20%~100%, 20%~90%, 20%~ 80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~ 30%, 30%~100%, 30%~90%, 30%~80%, 30%~70%, 30% ~60%, 30%~50%, 30%~40%, 40%~100%, 40%~90%, 40 %~80%, 40%~70%, 40%~60%, 40%~50%, 50%~100%, 5 0%~90%, 50%~80%, 50%~70%, 50%~60%, 60%~100%, 60%~90%, 60%~80%, 60%~70%, 70%~100%, 70%~90% , 70%~80%, 80%~100%, 80%~90%, 90%~100%, approximately the aforementioned - for any of the percentage ranges (e.g., about 10% to 70%, about 30% to 60%) In some embodiments, the control population In some embodiments, the control population is 18, 19, 20, 21 , 22, 23, 24, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 6 8, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 years old, or a range bounded by one of the above ages (e.g., 18-20, 25-35, 50-8 0, 50~70, 50~60, 55~75, 55~75, 55~70, 55~65, 60 Age equal to ~70, 52-71, 60-79, or 73-78 years, or 18-20 , 25~35, 50~80, 50~70, 50~60, 55~75, 55~ Over 70, 55-65, 60-70, 52-71, 60-79, or 73-78 years old In some embodiments, one or more CpG sites are Prim a1, Hsf4, Kcns1 genes and their combinations. In the present context, the methylation state referred to is the methylation of cytosine.

[0244] For procedural or other details supplementary to those set forth herein, see the references. More specifically described in the cited references incorporated herein.

[0245] The various methods and techniques described above provide some ways of practicing the present invention. Of course, not all of the stated objects or advantages may be achieved with the particular It should be understood that this may not necessarily be achieved according to the embodiment. The artisan will not necessarily achieve any other objectives or advantages that may be taught or suggested herein. rather, it is intended to achieve or optimize one advantage or group of advantages taught herein. It will be appreciated that the method may be carried out in accordance with the present invention.

[0246] Moreover, those skilled in the art will recognize the interchangeability of various features from different embodiments. Similarly, the various features and steps discussed above, and each such feature or step Other known equivalents of the floppy disk drive may be used by those skilled in the art to carry out methods according to the principles described herein. The mixing and matching can be done by one of ordinary skill in the art.

[0247] Although the present invention has been disclosed in the context of specific embodiments and examples, the present invention is not limited to the specific Other alternative embodiments and / or uses beyond those disclosed herein, as well as It will be understood by those skilled in the art that obvious modifications and equivalents of the present invention are covered. The disclosure is not intended to be limited by the specific disclosure of preferred embodiments herein. Instead, reference is intended to the claims appended hereto.

[0248] The following examples provide illustrations of some of the embodiments described herein, but are not intended to be limiting of the scope of the present invention. It is not intended to limit the scope of the present invention. [Example]

[0249] General experimental procedure Unless otherwise stated, the following general procedures were applied:

[0250] Mice. Mice included in the study were female C57BL / 6 and were obtained from an internal split stock. Obtained from The Jackson Laboratory and NIA / CharlesR C57BL / 6j mice obtained from both Iver and Janvier For the lifespan studies described herein, 70 Forty mice were randomly selected based on their age. Before the start of treatment (day 0), and on days 7 and 35 On day 1, mice were weighed and bled. Mice that did not recover from the blood draw and laboratory Mice that died due to errors were excluded. The animals were scored as "weak and dying" according to animal licensing protocols. Mice that had to be euthanized remained part of the data set. The allocation to treatment groups was random (20 mice per experimental group).

[0251] Median lifespans, 95% confidence intervals, and survival analyses were calculated using Prism GraphPadv 7.0c. Notably, the median lifespan of the control group was significantly higher than that of the various inbred strains. Data obtained for C57BL / 6j mice in a large set of mouse strain lifespan studies The young C57BL / 6 mice were 10 weeks old and housed in the same room and with the old mice. The animals were housed in a protected environment and setting. Animals were kept in accordance with the recommendations of the European Convention on the Protection of Animals from Violence (ETS 123). Macrolon Type II (long) cages with a maximum of four animals per cage The animals were housed in groups. The animals were fed food (V1124-3, ssniff®) The animals were kept on a 12 / 12-hour day / night rhythm throughout the experiment. Mouse experiments were conducted in accordance with European and German laboratory animal welfare laws. In accordance with approved protocols, the Institutional Review Board d of Ulm University and Regierungspraesidi Approved by um Tuebingen, Baden-Württemberg.

[0252] IP processing with CASIN solution. CASIN is a drug that is dissolved in beta-cyclodextrin. Freshly prepared prior to injection by dissolving directly in PEG-400 solution (Sigma #H5784) IP injections were performed every 24 hours in the morning for 4 consecutive days during the 75-week age of the mice. Control mice were injected with an equal volume of vehicle. Serum for cytokine arrays was collected from the bleeding point on day 7. Serum samples for mass spectrometry analysis of CASIN levels were prepared from 3 hours, 24 hours, and 100 mg / kg of CASIN at the end of treatment. Bleed equal (sex, strain, origin, and age) cohorts of mice for 10-48 h. The same CASIN stock was used throughout the study. It was provided as a dried powder.

[0253] Flow cytometry of peripheral blood (PB). Immunostaining of PB cells was performed according to standard procedures. The samples were analyzed using an LSRII flow cytometer (BD Biosciences). For PB lineage analysis, the antibodies used were obtained from eBioscience: anti-C D3ε (clone 145-2C11), anti-B220 (clone RA3-6B2), anti-Ma c-1 (clone M1 / 70) and anti-Gr-1 (clone RC57BL / 6-8C5) Lineage FACS analysis data were analyzed for B220+, CD3+, and myeloid (Gr-) leukocytes in total leukocytes. 1+, Mac-1+, and Gr-1+Mac-1+) cells as percentages WBC (white blood cells), RBC (red blood cells), Ly (lymphocytes), NE (neutrophils), and Mo (monocytes) were counted using a Hemavet 950 hemocytometer. Counting was performed using CInc, (FL33014), USA.

[0254] Liquid chromatography-mass spectrometry (LC-MS) analysis of CASIN pharmacokinetics in mouse serum / MS) measurement. Using an LC / MS / MS ion chromatography protocol, 0. Serum CASIN concentrations ranging from 1 to 10 μM were measured in mice injected i.p. at various times. Serum CASIN was spiked into mouse serum in vitro with a defined dose of CASIN. The standard curve was compared with that obtained using the autosampler maximum recovery vial with cap (Watt ers), UPLC-MS system (Water with ACQUITY UPLC system rsQuattroPremierXE mass spectrometry), AcquityBEHC18UPL C column (2.1 × 75 mm, 1.7 μm) (Waters), and AcquityB An EHC18UPLC guard column (Waters) was used. , Solvent A contained acetonitrile / water (5 / 95) containing 2 mM ammonium acetate; Solvent B contained acetonitrile / water (90 / 10). The gradient mobile phase was: From 60% solvent A to 57% solvent A in 2 minutes, to 50% solvent A in 2.1 minutes, and to 46% in 9.9 minutes. The solution switched to solvent A, changing to 30% in 12.1 minutes, then to 1% solvent A over 5.9 minutes, then to 1% solvent A over 5.9 minutes. The column temperature was maintained at 25°C. The capillary voltage for electrospray negative (ES-) mode was 3 kV, and the cone The voltage was 45 V, collision 30 V, and desolvation temperature 350°C. was 600 L / h, the source temperature was 120°C, and the MRM transition m / z was 305.1->244.

[0255] Cytokine array. Lumimex method. Cytokine concentrations in sample supernatants were , Milliplex™ Multiplex Kit (MilliporeSigma, (Darmstadt, Germany) according to the manufacturer's protocol. Briefly, in a 96-well black plate, 25 μL of duplicate samples were added. Incubate overnight at 4°C on a plate shaker with antibody-coated beads. Next, BioTek 405TS (BioTek, Winooski, VT) Wash the plate twice using PBS, add 25 µL of secondary antibody, and incubate at room temperature for 1 min with shaking. Finally, 25 μL of streptavidin-RPE was added to the secondary antibody. The plate was then incubated at room temperature for 30 minutes with shaking. After washing twice, 150 μL of sheath fluid was added. The plate was shaken for 5 minutes and then immersed in Mil liplexAnalyzer (MilliporeSigma, Darmstadt, Germany) The concentration was measured using luminex technology. The values ​​are calculated from a standard curve using the RT-PCR method and expressed in pg / ml.

[0256] Cdc42-GTPase effector domain pull-down assay. GTP-bound Cd The relative levels of c42 were determined by effector pull-down assay. Then, lineage-depleted BM cells (10 6 ) in 10% glycerol, 25 mM sodium fluoride thorium, 1 mM sodium orthovanadate and protease inhibitor cocktail (Ro cheDiagnostics) containing Mg 2+ Lysis / Wash Buffer (Upstate The samples were lysed in cell signaling solution (Cell Signaling Solution). The bound (activated) and unbound (non-activated) Cdc42 fractions were incubated with anti-C Immunoblotting using dc42 antibody (Millipore, rabbit polyclonal) Activated proteins were probed by β-glucanation. -Normalized to actin (Sigma) and relative amounts quantified by densitometry did.

[0257] Analysis of epigenetic signs of aging. CASIN(Xcessbio#M6004 0) was dissolved in DMSO at a concentration of 100 mM and added to a cyclodextrin solution (Sigma# The solution was prepared freshly before injection by diluting it with 25 mg / kg IP. The injections were administered in the morning for four consecutive days starting at 77–86 weeks of age. Control mice received an equal volume of vehicle. Mice were sacrificed 8–9 weeks after treatment, and blood was collected by cardiac puncture. Analysis of the level of cleavage was performed using three age-related CpG dinucleotides (CG dinucleotides) as previously described. Briefly, genomic DNA was isolated from blood samples and bisulfite-coated. Three genes (Prima1, Hsf4, and Kcns1) were transformed and isolated by pyrosequencing. DNA methylation at these sites was analyzed in B6 mice. Integrated into a multivariate model for epigenetic age prediction in humans and chronological age The chronological and biological ages of CASIN-treated and control mice were independently correlated. Comparisons were made using t-tests. Because the data were not normally distributed, All data were then augmented to obtain a normal distribution.

[0258] Example 1 To determine whether short-term systemic treatment of aged animals with a Cdc42-specific inhibitor modulates lifespan. To achieve this, CASIN was administered every 24 hours for 4 consecutive days to 75-week-old female C57BL / 6 mice. The serum CASIN levels were measured using liquid chromatography. -monitored by mass spectrometry (Figures 2a and 2b). At a single dose of 50 mg / kg, Initially, the serum concentration was approximately 10 μM (data not shown). A dose of 1 / kg was selected, and mass spectrometry data from serum of old mice was obtained 3 hours after injection. The CASIN concentration was 48 μM, which was in the expected range of 5 μM (Fig. 2b). The concentration decreased over the analysis window, reaching approximately 2 μM after 3 h and approximately 1 μM after 2 h. CASIN was detected in the serum at the end of the 48-hour window. There wasn't.

[0259] Four consecutive days of injection did not induce acute toxicity, and treatment was given within 4 weeks after CASIN injection. No mice died, so there was no concern about chronic toxicity due to the administration of the inhibitor. Quantification of Cdc42 activity 24 hours after the last injection on day 5 indicates that senescent showed that Cdc42-GTP in transformed bone marrow cells was reduced to the level seen in young animals ( Figure 1c), demonstrating that CASIN actually reduces Cdc42 activity after systemic in vivo treatment. As shown in Figure 1c, CASIN treatment significantly reduced the Cd damage regardless of the age of the mice. Furthermore, CASIN treatment reduced C42 activity by approximately half in the aged mouse cohort. Reverses dc42 activity to approximately the level seen in a control cohort of young mice Therefore, CASIN treatment generally reduces Cdc42 activity levels in aged mice by approximately 6 months. returned to levels present in 0-week-old young mice.

[0260] Notably, aged mice treated with CASIN for four consecutive days showed both average and maximum lifespans Therefore, treatment with a Cdc42-specific inhibitor was shown to be effective in preventing and alleviating the effects of drug therapy. despite being removed from the bloodstream immediately after cessation of treatment (e.g., long-term effects of short-term treatment) , which has a remarkable effect on extending lifespan, thereby showing lasting benefits from drug treatment. are.

[0261] In addition, weight (Fig. 2c), white blood cell count (WBC) (Fig. 2d), and red blood cell count (RBC) (Fig. 2e ), the frequency and number of myeloid and lymphoid cells in peripheral blood (PB) may increase in the short term (e.g., 7 days after starting treatment). Both in the 30 days (days) and long-term (e.g., 35 days after treatment initiation) did not change in response to CASIN treatment. It is also noteworthy that cytokine array analysis was performed to investigate the relationship between aging and senescence. Senescence-related inflammatory cytokines in the serum of aged mice were affected by CASIN treatment. The data showed that age-related changes in INFγ, IL-1β, and IL-1α The concentrations of these cytokines were significantly increased in aged animals. When treated with IN, the concentrations were similar to those in young animals (Fig. 1e-g). CASIN treatment reduces the concentrations of these cytokines, and without being bound by theory, This age-related decline in inflammatory cytokines may contribute to the increased lifespan observed in these animals. Interestingly, serum levels of IL-9 increased after CASIN treatment. IL-6, IL-2, GM-CSF, and LI were the only cytokines that were significantly affected (Fig. 1h). The concentrations of F, IL-4, and IL-7 tended not to increase significantly in aged mice. Although some of these (GM-CSF, IL-2) are also reduced by CASIN, many Tocainine concentrations were not altered by aging or CASIN treatment (Fig. 3).

[0262] CpG (5'-C-phosphate-G) in the Prima1, Hsf4, and Kcns1 genes DNA methylation status at -3' is a predictor of biological age in C57BL / 6 mice Therefore, DNA methylation profiling of these CpGs This C57BL / 6 mouse model has been investigated as a biological epigenetic clock. A panel of screened DNA methylation markers was analyzed in CASIN-treated aged animals. When applied to blood cells after 9 weeks, epigenetic age predictions were timed to match those of aged control animals. Instead, we observed that the Cdc42-specific inhibitors no longer correlated with lineage age. Treatment with α-glucan resulted in a predicted biological age that was on average 9 weeks younger than the mice's chronological age ( Therefore, mice treated with Cdc42-specific inhibitors (e.g., CASIN) Without being bound by any theory, the authors conclude that the observed changes in aged CASIN-treated mice These findings indicate epigenetic changes that may influence the increased lifespan observed.

[0263] In addition, obesity, metabolic syndrome, diabetes, cardiovascular disease, cancer, depression, and Alzheimer's Many age-related diseases, such as sarcopenia, share an inflammatory etiology, and activation of inflammatory pathways contributes to sarcopenia. Without being bound by theory, these The elevated levels of interferon gamma detected in the experiment are characteristic of maintaining youth. Similarly, interleukin-1α and interleukin-2α may be functionally related to lifespan. Both leukin-1β and leukin-1β are associated with many age-related phenotypes and diseases. Regarding IL-9, which showed increased serum concentrations after treatment, IL-9 is mainly a T helper 9 It is a pleiotropic cytokine produced by Th9 cells and is expressed by lymphocytes, mast cells, and exerts documented effects on resident lung cells. Without being bound by any theory, The data presented here support the role of high concentrations of these cytokines in regulating lifespan. The data further suggest a role for Prima1, Hsf4, and K in blood cells. The methylation status of CpG sites within the cns1 gene is strongly correlated with biological age, and C57BL / 6 mice and has been shown to function as a validated biomarker of aging.

[0264] As mentioned above, the data herein support the decline in Cdc42 activity in aged mice. Here we show that CASIN actually extends lifespan. Inhibition of mTOR by rapamycin and inhibition of mTOR by rapamycin are already quite late in life (over 75 weeks of age). administered and only temporarily (only 4 days for CASIN and 90 days for rapamycin) The only reported pharmacological treatment that significantly affects the lifespan of mice when administered daily (days) This is because the mechanism of action of CDC42-specific inhibitors is that they are usually administered early in life. and / or other life-span measures provided continuously over an extended period to achieve significant benefits. This indicates that it is different from pharmacological interventions for

[0265] Example 2 The experimental setup for the vaccination response experiment is shown in Figure 5(A). C57BL / 6 mice (referred to as "aged" in the results) and 12- to 16-week-old mice (referred to as "aged" in the results). In this study, mice (called "young") were given a desired dose (e.g., 25 mg / kg) of Cdc42-specific Inhibitors (e.g., CASIN) or vehicle (referred to as "vehicle" in the results) as controls Mice were injected intraperitoneally ("IP") every 24 hours for 4 days. On day 5, mice were treated with 5-fluorouracil. The mice were treated with Rasil ("5-FU"). Two methods of vaccination were investigated.

[0266] For DNA vaccination: 12 weeks after transplantation, recipient mice were infected with hepatitis B virus. The mice were immunized with pCI / cDNA encoding the hepatitis B virus (HBV) core antigen. The results of DNA vaccination with HBV core antigen 13 days after the immunization and ovalbumin ( "Ova" specific immune response. Interferon gamma positive CD3 + CD8 + Analyze the frequency of T cells, which is an established parameter for the success of DNA vaccination protocols. As shown in Figure 5(B), all mice were immunized with HBV core antigen. Post-vaccination interferon-gamma positive CD3 + CD8 + The frequency of T cells was increased. Aged mice treated with ASIN showed a statistically significant increase in immune response. n = 1 experiment *p<0.05 Aged vehicle vs. Aged CASIN. Figure 5(C) , splenic K b / C 93-100 -Dimer + CD8 + T cell frequency and HBV core antigen These T cell frequencies were determined by flow cytometry 13 days after immunization with It is a direct measure of antigen-specific T cells. Aged mice treated with CASIN showed a higher number of antigen-specific T cells. The results showed a statistically significant increase in target T cells. n = at least 3 per experiment. *p<0.05 Aged Solvent vs. Aged CASIN.

[0267] For viral vaccination, animals were given an intramuscular injection 12 weeks after CASIN treatment. Inactivated influenza virus (10 μg H3N2 + 10 μL Al(OH)3) The animals were immunized twice at an interval of 4 weeks with the second vaccine. The antibody titers were measured using ELISA technology. The results were obtained from serum samples taken 21 days after vaccination. n = at least 3 per experiment. As shown in Figure 5(D), this was compared to vehicle-treated aged mice as a control cohort. The results show that the antibody titer in aged mice treated with CASIN is increased. Aged mice treated with CASIN showed significantly higher phenotypes than young mice, regardless of CASIN treatment within that cohort. This suggests that the antibody titers were approximately equivalent to those seen in older mice.

Claims

1. 1. A method for extending the lifespan of a subject, comprising administering to a subject in need thereof an effective amount of at least one The method comprises administering a Cdc42-specific inhibitor of

2. 1. A method for increasing survival time in a subject, comprising administering to a subject in need thereof an effective amount of at least A method comprising administering one Cdc42-specific inhibitor.

3. 1. A method of extending the lifespan of a subject, comprising administering to a subject in need of treatment an effective amount of at least and administering at least one Cdc42-specific inhibitor.

4. 1. A method of extending the health span of a subject, comprising administering to a subject in need of treatment an effective amount of at least administering another Cdc42-specific inhibitor.

5. A method of immunizing a subject, comprising administering to a subject in need thereof an effective amount of at least one administering a Cdc42-specific inhibitor, and administering one or more immunization doses to said subject. A method, comprising:

6. The subject can be defined as an extension of lifespan, an extension of survival time, an extension of life span, an extension of health span, or any one of claims 1 to 5, further comprising identifying said subject as one that would benefit from immunization.

10. The method according to claim 1.

7. The subject is screened for the following: the subject's age, the subject's current medical condition, the subject's current medical treatment; or the subject is identified based on Cdc42 activity.

8. The Cdc42-specific inhibitor is administered to the subject before the subject receives one or more immunization doses. The method according to any one of claims 5 to 7, wherein the method is administered to

9. The Cdc42-specific inhibitor is administered to the subject after the subject has received one or more immunization doses. The method according to any one of claims 1 to 8, wherein the medicament is administered to

10. The subject is administered a first Cdc42-specific inhibitor, and the subject is administered the first Cdc42-specific inhibitor. 42 specific inhibitor, and then a first immunization is administered to the subject, and the subject receives the first immunization.

10. The method of claim 1, wherein the subject receives one or more subsequent immunization doses after the administration of the vaccine. The method described below.

11. After the subject receives the second immunization dose, the subject receives a third immunization dose. The method according to any one of claims 1 to 10.

12. The subject receives a total of 1 to 10, 1 to 9, 1 to 8, １～７、１～６、１～５、１～４、１～３、２～１０、２～９、２～８、２～７、２～６ , 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7 times, 3-6, 3-5, 3 ～４、４～１０、４～９、４～８、４～７、４～６、４～５、５～１０、５～９、５～８ 、５～７、５～６、６～１０、６～９、６～８、６～７、７～１０、７～９、７～８、８ 12. Any one of claims 1 to 11, wherein the vaccine is administered up to 10, 8 to 9, or 9 to 10 immunization doses. The method described below.

13. The subject receives a total of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 13. The method according to any one of claims 1 to 12, wherein the mouse receives 10 or 10 immunization doses.

14. The method of any one of claims 1 to 13, wherein the subject is immunized against multiple diseases. 。

15. The period between the immunizations may be about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, or about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, The method of any one of claims 1 to 14, wherein the period is about 11 months or about 1 year.

16. The subject is administered a second Cdc42-specific inhibitor after receiving the first immunization. The method according to any one of claims 1 to 15,

17. 10. The method of claim 1, wherein the subject is administered a Cdc42-specific inhibitor prior to one or more immunization doses.

17. The method according to any one of 1 to 16.

18. 10. The method of claim 1 , wherein the subject is administered a Cdc42-specific inhibitor after one or more immunization doses.

18. The method according to any one of 1 to 17.

19. 1. The first and second Cdc42-specific inhibitors of claim 1, wherein the first and second Cdc42-specific inhibitors are the same or different.

9. The method according to any one of claims 8 to 8.

20. 20. The method according to any one of claims 1 to 19, wherein the first and second immunizations are the same or different. How to post.

21. The method of any one of claims 1 to 20, wherein the subject's immune system is compromised.

22. The subject's immune system may be affected by factors such as the subject's age, the subject's condition, or the subject's resistance to the condition.

22. The method of any one of claims 1 to 21, wherein the subject is rendered susceptible to infection by treatment with 。

23. The method of any one of claims 1 to 22, wherein the immunization is a vaccine.

24. The vaccine is approved by the Centers for Disease Control and Prevention (CDC). The method according to claim 23 is recommended by the National Institute of Health and Prevention. The method described.

25. The vaccination is for influenza, whooping cough, tetanus, diphtheria, shingles, pneumonia, Coccal disease, human papillomavirus, meningococcal disease, hepatitis A, hepatitis B, chickenpox, measles , mumps, and rubella.

25. The method according to claim 23 or 24.

26. The method of any one of claims 1 to 22, wherein the immunization is not a vaccine.

27. The method of any one of claims 1 to 26, wherein the administration is systemic.

28. The method of any one of claims 1 to 26, wherein the administration is topical.

29. The method of any one of claims 1 to 28, wherein the subject is an elderly human subject.

30. The subject is 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, ６１、６２、６３、６４、６５、６６、６７、６８、６９、７０、７１、７２、７３、７ 4, 75, 76, 77, 78, 79, 80 years of age or older, according to claims 1 to 2.

10. The method according to any one of claims 9 to 10.

31. 30. The method of claim 1, wherein the administration of the Cdc42-specific inhibitor to the subject is performed once.

10. The method according to any one of the preceding claims.

32. 32. The method of claim 1, wherein the administration of the Cdc42-specific inhibitor is performed two or more times.

1. The method according to claim 1.

33. The administration of the Cdc42-specific inhibitor is 1 to 10 times, 1 to 9 times, 1 to 8 times, 1 to 7 times, , 1-6 times, 1-5 times, 1-4 times, 1-3 times, 2-10 times, 2-9 times, 2-8 times, 2-7 times times, 2-6 times, 2-5 times, 2-4 times, 2-3 times, 3-10 times, 3-9 times, 3-8 times, 3- 7 times, 3-6 times, 3-5 times, 3-4 times, 4-10 times, 4-9 times, 4-8 times, 4-7 times, 4 Up to 6 times, 4-5 times, 5-10 times, 5-9 times, 5-8 times, 5-7 times, 5-6 times, 6-10 times , 6-9 times, 6-8 times, 6-7 times, 7-10 times, 7-9 times, 7-8 times, 8-10 times, 8- 33. The method of any one of claims 1 to 32, performed 9 times, or 9 to 10 times.

34. The administration of the Cdc42-specific inhibitor is 2, 3, 4, 5, 6, 7, 8, 9, or 1 34. The method of any one of claims 1 to 33, wherein the method is performed 0 times.

35. The administration is from the group consisting of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, and 8 days.

35. The method of any one of claims 1 to 34, which is administered as a selected daily regimen. 。

36. The administration may be continued for about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 6 months, or months, about 9 months, about 1 year, about 5 years, about 10 years, or about the remaining life span of said subject 36. The method according to claim 1, wherein the administration is carried out as a non-consecutive day regimen selected from the group consisting of: The method described in paragraph .

37. The regimen may be administered about weekly, about monthly, about every 6 months, about every 9 months, or about every 12 months. and repeated about every two years or about every five years, How to post.

38. The Cdc42 activity in the subject is measured prior to administering the Cdc42-specific inhibitor. The method of any one of claims 1 to 37, wherein the temperature is determined.

39. The Cdc42 activity in the subject is measured prior to each administration of the Cdc42-specific inhibitor. The method of any one of claims 1 to 38, wherein the temperature is determined.

40. The regimen or administration is repeated based on the Cdc42 activity in the subject. The method according to any one of claims 1 to 39,

41. The Cdc42 activity in the subject is determined by first administering the Cdc42-specific inhibitor to the subject. about 25%, about 30%, about 40% of the Cdc42 activity in the subject prior to administration to the elephant , about 50%, about 55%, about 60%, about 70%, about 80%, about 90%, about 100%, about 10 5%, about 110%, about 115%, about 120%, or about 125% of the Cd 41. The method of claim 1, wherein the regimen or administration of the c42-specific inhibitor is repeated.

1. The method according to claim 1.

42. The method of claim 1, wherein the Cdc42 activity level in the subject is restored to a normal level in the subject.

41. The method of any one of claims 41 to 41.

43. Any of claims 1 to 42, wherein Cdc42 is inhibited in blood progenitor cells of the subject.

10. The method according to claim 1.

44. 44. The method of claim 43, wherein the blood progenitor cells are hematopoietic cells.

45. 45. The method of claim 44, wherein the hematopoietic cells are selected from the group consisting of progenitor cells and stem cells. How to do it.

46. The method according to any one of claims 1 to 45, wherein the intracellular tubulin nonpolarity is reversed. How to post.

47. 47. The method of any one of claims 1 to 46, wherein the subject is a mammal or a human.

48. The expected increase is related to the subject's expected lifespan, survival time, life span, or For the health span, about 1% to 100%, about 1% to 90%, about 1% to 80%, about 1% to 7 0%, about 1% to 60%, about 1% to 50%, about 1% to 40%, about 1% to 30%, about 1% to 2 48. The method of any one of claims 1 to 47, wherein the concentration is 0%, or about 5% to 15%.

49. The expected increase is related to the subject's expected lifespan, survival time, life span, or For the healthy span, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, Any one of claims 1 to 48, wherein the solubility is about 12%, about 13%, about 14%, or about 15%. The method described below.

50. The expected increase is related to the subject's expected lifespan, survival time, life span, or For a health span, at least about 1 to 20 years, at least about 1 to 19 years, at least about 1 to 18 years, at least about 1 to 17 years, at least about 1 to 16 years, at least about 1 to 15 years years, at least about 1-14 years, at least about 1-13 years, at least about 1-12 years, at least at least about 1 to 11 years, at least about 1 to 10 years, at least about 1 to 9 years, at least about 1 up to 8 years, at least about 1-7 years, at least about 1-6 years, at least about 1-5 years, at least In either case, the aging time is about 1 to 4 years, at least about 1 to 3 years, at least about 1 to 2 years, or at least about 1 year.

50. The method of any one of claims 1 to 49, wherein the

51. The expected increase is related to the subject's expected lifespan, survival time, life span, or For the health span, about 1 to 20 years, about 1 to 19 years, about 1 to 18 years, about 1 to 17 years, about 1 ~16 years, about 1-15 years, about 1-14 years, about 1-13 years, about 1-12 years, about 1-11 years, About 1-10 years, about 1-9 years, about 1-8 years, about 1-7 years, about 1-6 years, about 1-5 years, about 1- 4 years, about 1 to 3 years, about 1 to 2 years, or about 1 year, according to any one of claims 1 to 50. The method described.

52. The expected increase is related to the subject's expected lifespan, survival time, life span, or For a healthy span, at least about 1 day to 1 year, at least about 1 day to 11 months, at least about 1 day to 10 months, at least about 1 day to 9 months, at least about 1 day to 8 months, at least Also about 1 day to 7 months, at least about 1 day to 6 months, at least about 1 day to 5 months, at least About 1 day to 4 months, at least about 1 day to 3 months, at least about 1 day to 2 months, or at least 52. The method of any one of claims 1 to 51, wherein both the treatment and the dialysis are for about 1 day to 1 month.

53. The expected increase is related to the subject's expected lifespan, survival time, life span, or For a health span, at least about 1-52 weeks, at least about 2-50 weeks, at least at least about 3 to 45 weeks, at least about 4 to 40 weeks, at least about 5 to 35 weeks, at least About 6 to 30 weeks, at least about 5 to 25 weeks, at least about 6 to 20 weeks, at least about 7 to 19 weeks, at least about 8 to 18 weeks, at least about 9 to 17 weeks, at least about 1 0-16 weeks, at least about 11-15 weeks, or at least about 12-14 weeks 53. The method according to any one of claims 1 to 52.

54. The expected increase is related to the subject's expected lifespan, survival time, life span, or For a healthy span, approximately 1-52 weeks, approximately 2-50 weeks, approximately 3-45 weeks, and approximately 4-40 weeks About 5 to 35 weeks, about 6 to 30 weeks, about 5 to 25 weeks, about 6 to 20 weeks, about 7 to 19 weeks about 8 to 18 weeks, about 9 to 17 weeks, about 10 to 16 weeks, about 11 to 15 weeks, or about 54. The method of any one of claims 1 to 53, wherein the treatment is for 12 to 14 weeks.

55. The expected increase is related to the subject's expected lifespan, survival time, life span, or For a healthy span, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, About 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, approximately 15 weeks, approximately 16 weeks, approximately 17 weeks, approximately 18 weeks, approximately 19 weeks, approximately 20 weeks 55. The method of claim 1, wherein the duration of administration is about 21 weeks, about 22 weeks, about 23 weeks, or about 21 weeks. The method according to any one of claims 1 to 4.

56. The expected increase is related to the subject's expected lifespan, survival time, life span, or For the health span, about 1 day to 1 year, about 1 day to 11 months, about 1 day to 10 months, about 1 day to 9 months months, about 1 day to 8 months, about 1 day to 7 months, about 1 day to 6 months, about 1 day to 5 months, about 1 day to 4 months 55. The method of claim 1, wherein the period is about 1 day to 3 months, about 1 day to 2 months, or about 1 day to 1 month.

10. The method according to any one of the preceding claims.

57. The method of any one of claims 1 to 56, wherein the predicted increase is statistically significant. Law.

58. The expected lifespan, survival time, lifespan, or healthspan of the subject is similarly 58. The method of any one of claims 1 to 57, wherein the median predicted value of subjects in the state.

59. The expected lifespan, survival time, lifespan, or healthspan of the subject is similarly 59. The method of any one of claims 1 to 58, wherein the mean predicted value for subjects in the condition.

60. 60. The method of claim 1, wherein the effective amount of a Cdc42-specific inhibitor does not mobilize hematopoietic progenitor cells.

10. The method according to any one of claims 1 to 9.

61. 10. The method of claim 1, wherein the Cdc42-specific inhibitor is administered as a pharmaceutically acceptable composition.

61. The method according to any one of claims 1 to 60.

62. The pharmaceutically acceptable compositions include tablets, suspensions, solutions, and emulsions.

62. The method of claim 61 , selected from the group:

63. 63. The method of claim 61 or 62, wherein the pharmaceutically acceptable composition is administered orally. 。

64. 63. The method of claim 61 or 62, wherein the pharmaceutically acceptable composition is administered by injection. How to post.

65. 63. The method of claim 61 or 62, wherein the pharmaceutically acceptable composition is administered by infusion. How to post.

66. The pharmaceutically acceptable composition is formulated so as not to reduce Cdc42 activity below normal levels.

66. The method according to claim 61, wherein the Cdc42-specific inhibitor is present in a combined dose. How to do it.

67. The ratio of Cdc42-GTP to total Cdc42 levels in the subject is Previous approximately 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1 ．９、２．０、２．１、２．２、２．３、２．４、２．５、２．６、２．７、２．８、２ 67. The method of any one of claims 1 to 66, wherein the β-glucan content is 0.9, 1.0, 1.2, 1.3, 1.4, 1.6, 1.8, 1.9, or 3.

0.

68. At least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the subjects %, 80%, and 90% of the blood progenitor cells have a total C of Cdc42-GTP before the administration 68. The method of claim 67, wherein the ratio is relative to dc42 levels.

69. The ratio of the Cdc42-GTP to total Cdc42 level in the blood progenitor cells 69. The method of any one of claims 67-68, wherein is decreased after said administration.

70. The ratio of the Cdc42-GTP to total Cdc42 level in the blood progenitor cells is less than about 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 after said administration 70. The method according to any one of claims 1 to 69.

71. The total Cdc42 of the Cdc42-GTP in the hematopoietic progenitor cells or epithelial progenitor cells the ratio to the level is at least about 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.1, 3.

71. The method of any one of claims 1 to 70, wherein the number of ions is 2 or more.

72. and further comprising discontinuing the exposure of the subject to the Cdc42-specific inhibitor. and the Cdc42-specific inhibitor-mediated changes in the subject are maintained after exposure is discontinued. The method according to any one of claims 1 to 71,

73. The method according to any one of claims 1 to 72, wherein the Cdc42-specific inhibitor is CASIN. method.

74. The Cdc42-specific inhibitor may be a single enantiomer, a mixture of enantiomers, or a drug and a compound of formula (I) as a physiologically acceptable salt, solvate, or polymorph thereof, 【Chemical 1】 During the ceremony, Y is -OR ７ , -NR ８ R ９ , and -NNR ８ R ９ is selected from the group consisting of R ７ is C １～６ Alkyl, -(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Arke Nill, C. １～６ Alkoxy, hydroxy-C １～６ Alkyl, phenyl, up to 5 full C substituted with Oro １～６ C substituted with alkyl and up to 5 fluoro １～６ a alkoxy, １～６ Alkyl, -(CH ２ ) ｕ C ３～７ Shik Roalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, hydroxy-C １～６ Alkyl , phenyl are each optionally selected from halo, —CN, —OH, C １～６ Alkoxy, hetero Aryl, R １９ , and -OR ２０ one or more independently selected from the group consisting of is substituted with the above substituents, R ８ and R ９ are each independently hydrogen or R ２０ or R ８ and R ９ optionally together with the nitrogen to which they are attached, form indolinyl, pyrrolidinyl , piperidinyl, piperazinyl, or morpholinyl, each of which is selected from the group consisting of halo, cyano, No, nitro, hydroxy, C １～６ Alkyl, (CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, hydroxy-C １～６ Alkyl, phenyl, Five fluoro-substituted C １～６ C substituted with alkyl and up to 5 fluoro １ ～６ and optionally substituted with one or more substituents each independently selected from the group consisting of: alkoxy; or R ８ and R ２ are joined together to form a ring; １ ～３ And Each R ２０ is C １～６ Alkyl, C ３～７ the group consisting of cycloalkyl, and phenyl and wherein said C １～６ Alkyl, C ３～７ Cycloalkyl, and phenyl are each independently R ２１ and R ２２ one or more substituents selected from the group consisting of optionally replaced by Each R ２１ are independently selected from the group consisting of halo, cyano, nitro, and hydroxy. And, Each R ２２ separately, C １～６ Alkyl, C １～６ Alkoxy-(CH ２ ) ｕ C ３～ ７ Cycloalkyl, C ２～６ Alkenyl, Hydroxy C １～６ Alkyl, R １９ and- OR ２０ and each is selected from the group consisting of halo, cyano, nitro, hydroxy, C １～６ Alkyl, and C １～６ alkoxy optionally substituted with one or more substituents; each u is independently 0, 1, 2, 3, or 4; R ２ is hydrogen or C １～６ Alkyl, C ３～７ Cycloalkyl, and phenoxy wherein C is selected from the group consisting of １～６ Alkyl, C ３～７ cycloalkyl, and Phenyl is independently selected from halo, cyano, nitro, hydroxy, C １～６ Alkyl, - (CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, hydroxy Droxy-C １～６ C substituted with alkyl, phenyl, up to 5 fluoro １～６ Al Kill, C substituted with up to 5 fluoro １～６ Alkoxy and, each independently, halides Ro, cyano, nitro, hydroxy, C １～６ Alkyl, and C １～６ Alkoxy? -O(CH ２ ) ｕ Phenyl or R ８ and R ２ are joined together to form a ring; １～３ And R ３ , R ４ , R ５ and R ６ are each independently hydrogen, halo, cyano, nitro, or hydro Roxi, C １～６ Alkyl, (CH ２ ) ｕ C ３～７ cycloalkyl, —O(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, hydroxy-C １～ ６ C substituted with alkyl, phenyl, up to 5 fluoro １～６ Alkyl, and max. Five fluoro-substituted C １～６ alkoxy, wherein C １～６ Alkyl, (CH ２ ) ｕ C ３～７ cycloalkyl, —O(CH ２ ) ｕ C ３～７ Cycloal Kill, C ２～６ Alkenyl, C １～６ Alkoxy, hydroxy-C １～６ Alkyl and and phenyl each optionally have one or more R ２３ is replaced by Each R ２３ are independently halo, cyano, nitro, hydroxy, C １～６ Alkyl, -( CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, Hydro Kishi-C １～６ C substituted with alkyl, phenyl, up to 5 fluoro １～６ Alkyl and C substituted with up to five fluoro １～６ alkoxy; The phenyl may be selected from halo, cyano, nitro, hydroxy, C １～６ Alkyl, -(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, hydroxy-C １～６ C substituted with alkyl, phenyl, up to 5 fluoro １～６ alkyl, and C substituted with up to 5 fluoro １～６ Independently selected from the group consisting of alkoxy optionally substituted with substituents, Each R １９ are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups, optionally C replaced by １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy is an aryl group, Each R ２０ are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups, optionally C replaced by １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy is hydrogen or aryl, Y is NR ８ R ９ If R ８ and R ２ can be arbitrarily joined together to form a ring. Bonding alkyl C １～３ However, However, R ８ is R ２ Alkyl C １～３ became In this case, R ４ is not substituted with hydroxyl.

1. The method according to claim 1.

75. R ３ , R ４ , R ５ and R ６ wherein one, two, or three of 74. The method according to claim 74.

76. R ４ But C １～６ Alkyl, -(CH ２ ) ｕ C ３～７ cycloalkyl, —O(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, phenyl, max Five fluoro-substituted C １～６ Alkyl and substituted with up to 5 fluoro C １～６ alkoxy, wherein C １～６ Alkyl, -(CH ２ ) ｕ C ３～７ cycloalkyl, —O(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl , C １～６ Alkoxy and phenyl are each haloC １～６ Alkyl, -(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, hydroxy- C １～６ C substituted with alkyl, phenyl, up to 5 fluoro １～６ Alkyl and and C substituted with up to 5 fluoro １～６ one or more selected from the group consisting of alkoxy 76. The method of claim 74 or 75, optionally substituted with the above substituents.

77. During the ceremony, Y is -NR ８ R ９ and R ８ is hydrogen, and R ９ is hydroxyl, R １９ and -OR ２０ From the group consisting of C, each optionally substituted with one or more independently selected substituents １～６ With alkyl can be, Each R １９ is independently a C optionally substituted with halo, cyano, or up to five fluoro groups; １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ The group consisting of alkoxy and Each R ２０ are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups, optionally C replaced by １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy 77. The method of any one of claims 74 to 76, wherein the alkyl group is hydrogen or phenyl.

78. During the ceremony, Each R １９ Ha, Halo, C １～６ Alkyl, and C １～６ from the group consisting of alkoxy are independent phenyls, each optionally substituted with one or more independently selected substituents; Each R ２０ Ha, Halo, C １～６ Alkyl, and C １～６ from the group consisting of alkoxy are independent phenyls, each optionally substituted with one or more independently selected substituents; 78. The method or pharmaceutical composition of any one of claims 74 to 77.

79. R ２ and R ８ The method of any of claims 74 to 78, wherein is hydrogen.

80. Y is -NR ８ R ９ and R ８ and R ２ C joins together to form a ring １ ～３ 80. The method of any one of claims 74 to 79, wherein the alkyl group is alkyl.

81. R ９ The method of any one of claims 74 to 80, wherein is hydrogen.

82. R ９ But hydroxy, R １９ or -OR ２０ each independently selected from the group consisting of C optionally substituted with one or more substituents １～６ is alkyl, Each R １９ is independently a C optionally substituted with halo, cyano, or up to five fluoro groups; １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ The group consisting of alkoxy and Each R ２０ are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups, optionally C replaced by １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy The method of any one of claims 74 to 80, wherein the alkyl group is hydrogen or phenyl.

83. R ９ is hydrogen or C １～６ alkyl, hydroxyl, R １９ and -OR ２０ mosquito and optionally substituted with one or more substituents each independently selected from the group consisting of: Each R １９ is independently a C optionally substituted with halo, cyano, or up to five fluoro groups; １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ The group consisting of alkoxy and Each R ２０ are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups, optionally C replaced by １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy The method of any one of claims 74 to 80, wherein the alkyl group is hydrogen or phenyl.

84. In the formula, R ４ is C １～６ Alkyl, -(CH ２ ) ｕ C ３～７ cycloalkyl, —O(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, phenyl, C substituted with up to 5 fluoro １～６ Alkyl and up to 5 fluoro substituted C １～６ alkoxy, wherein C １～６ Alkyl, -(CH ２ ) ｕ C ３～７ cycloalkyl, —O(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Arke Nill, C. １～６ Alkoxy and phenyl each optionally contain one or more R ２３ Replace with And, Each R ２３ are independent, halo, C １～６ Alkyl, -(CH ２ ) ｕ C ３～７ cycloalkyl , C ２～６ Alkenyl, C １～６ substituted with alkoxy, phenyl, up to 5 fluoro TaC １～６ C substituted with alkyl and up to 5 fluoro １～６ From alkoxy wherein said phenyl is selected from the group consisting of halo, C １～６ Alkyl, -(CH ２ ) ｕ C ３～７ Cycloalkyl, C ２～６ Alkenyl, C １～６ Alkoxy, substituted with up to 5 fluoro C １～６ C substituted with alkyl and up to 5 fluoro １～６ Alkoxy? Optionally substituted with substituents independently selected from the group consisting of:

1. The method according to claim 1.

85. R ４ But C １～６ Alkyl, C ３～７ Cycloalkyl, —OC ３～７ cycloalkyl, Phenyl, C substituted with up to 5 fluoro １～６ Alkyl, and up to five fluoro C substituted with b １～６ alkoxy, wherein said phenyl is selected from the group consisting of halo, C １～６ Alkyl, C １～６ Alkoxy, C substituted with up to 5 fluoro １～６ Archi C substituted with up to five fluoro groups １～６ each from the group consisting of alkoxy Any of claims 74 to 84, optionally substituted with one or more independently selected substituents.

10. The method according to claim 1.

86. Y is -NR ８ R ９ and R ８ and R ２ C joins together to form a ring １ ～３ The method of any one of claims 74 to 85, wherein the alkyl group is alkyl.

87. R ２ is hydrogen or C １～６ Alkyl, C ３～７ Cycloalkyl, and C is selected from the group consisting of phenyl, １～６ The alkyl is optionally substituted with one or more halo. The method of any one of claims 74 to 86, wherein

88. R ２ The method of any one of claims 74 to 87, wherein is hydrogen.

89. R ９ is hydrogen or C １～６ alkyl, hydroxyl, R １９ and -OR ２０ mosquito and optionally substituted with one or more substituents each independently selected from the group consisting of: Each R １９ is independently a C optionally substituted with halo, cyano, or up to five fluoro groups; １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ The group consisting of alkoxy and Each R ２０ are independently halo, cyano, nitro, hydroxy, and up to five fluoro groups, optionally C replaced by １～６ C optionally substituted with alkyl and up to 5 fluoro １～６ Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy The method of any one of claims 74 to 88, wherein the alkyl group is hydrogen or phenyl.

90. 90. The compound of formula (I) according to any one of claims 74 to 89, wherein the compound is selected from the group consisting of: The method described in paragraph . 【Chemistry 2】

91. The effective amount of the Cdc42-specific inhibitor is administered to the subject to treat one or more circulating inflammatory 91. The method of any one of claims 1 to 90, wherein the amount of a cytokine is reduced.

92. the effective amount of the Cdc42-specific inhibitor inhibits the induction of interferon gamma in the subject; One or more selected from the group consisting of interleukin 1α and interleukin 1β The method according to any one of claims 1 to 91, which reduces the amount of circulating inflammatory cytokines in Law.

93. the effective amount of the Cdc42-specific inhibitor inhibits the induction of interferon gamma in the subject; Claims 1 to 92: Reducing the amount of interleukin 1α and interleukin 1β A method according to any one of the preceding claims.

94. The effective amount of the Cdc42-specific inhibitor increases circulating interleukin (I) levels in the subject. The method of any one of claims 1 to 93, wherein the amount of kin9 is increased.

95. The subject has a gene selected from the group consisting of Prima1, Hsf4, and Kcns1. Any one of claims 1 to 94, selected based on the methylation status of CpG sites in the gene. The method described in paragraph .

96. The subject has a CpG sequence in each of the Prima1, Hsf4, and Kcns1 genes.

96. The method of any preceding claim, wherein the selection is based on the methylation status of the site.

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