Combination therapy for treating cancer

Abstract

The present invention relates to the combination of specific benzenesulfonamide thiazole compounds with an anti-cancer therapy for use in the treatment of cancer in patients identified as overexpressing GRP78. Using a colorectal cancer mouse model (CT26 allograft model) and several in vitro cancer cell line models, the present inventors have shown that the cancer cell lines are more stable than monotherapies comprising either a benzsulfamide thiazole compound or an anti-cancer agent alone, as compared to monotherapies comprising a benzsulfamide thiazole compound or an anti-cancer agent alone. Combination therapies using HA15 (benzenesulfonamide thiazole compounds) and anti-cancer therapies, such as immunotherapeutic, chemotherapeutic or targeted therapies, significantly increase survival and strongly reduce tumor growth.

Description

Technical Field

[0001] The present invention relates to novel cancer therapies. In particular, the present invention relates to the combination of an anticancer therapy with a benzenesulfonamide thiazole compound for use in treating cancer in a patient who has been identified as overexpressing GRP78. Background Art

[0002] Cancer encompasses a large class of diseases characterized by uncontrolled cell growth and division. More than 200 known forms of cancer collectively impose a daunting societal burden in terms of loss of life, reduced quality of life, health care costs, and reduced productivity. Over the past decade, significant improvements have been made in the diagnosis, screening, and treatment of cancer. However, cancer remains the leading cause of death worldwide: it killed nearly 10 million people in 2020 (Ferlay et al. Global Cancer Observatory: Cancer Today. Lyon: International Agency for Research on Cancer; 2020).

[0003] Many types of cancer treatments have been developed and are available, such as chemotherapy, radiation therapy, and immunotherapy.

[0004] Chemotherapy is usually part of the first-line anticancer regimen. Despite showing good results in a large number of cancers, it is also accompanied by several side effects that can strongly impair the patient's quality of life. Close management of the applied dose and regimen is necessary to optimize the chances of remission and maintain the patient's health.

[0005] It has also been shown that the development of targeted therapies that specifically target genes and molecules that are directly involved in carcinogenesis and tumor growth is extremely useful. These therapies are a form of personalized medicine, and in contrast to traditional chemotherapy, they do not "simply" target any rapidly dividing cells. Therefore, it is assumed that patients tolerate targeted therapies better. Unfortunately, the identification of suitable molecular targets is still in progress, and the development of corresponding drugs takes a lot of time.

[0006] Immunotherapy is now a recognized and mature therapeutic option for the treatment of cancer. It combines several different therapies, all based on stimulating the patient's immune system to recognize and attack his or her disease. Immunotherapy using immune checkpoint regulators has revolutionized the field of oncology (Robert, C. Nat Commun 11, 3801, 2020). The origin of this therapy concept led to James P. Allison and Tasuku Honjo winning the 2018 Nobel Prize in Medicine. Immune checkpoints refer to a large number of inhibitory pathways hardwired into the immune system, which are crucial for maintaining self-tolerance and regulating the duration and amplitude of physiological immune responses in peripheral tissues to minimize indirect tissue damage caused by immune responses. When checkpoints and their ligands are combined, they send "off" signals to T cells, thereby inhibiting / strongly reducing immune responses. It is now clear that tumors use certain immune checkpoint pathways to escape immune responses. Immune checkpoint inhibitors (ICIs) work by blocking the binding of checkpoints to their ligands, thereby preventing the "off" signal from being sent. These compounds have shown significant clinical efficacy and represent substantial hope for curing some treatment-resistant tumors. Unfortunately, not all tumors respond to immune checkpoint inhibitors. In some cases, the immune system simply fails to detect and attack the tumor even after the inhibitory signals sent by the immune checkpoints have been turned off. Some tumors are actually non-immunogenic, meaning that they cannot be detected by immune cells. The immunogenicity of a tumor depends on its antigenicity and several other immune regulatory factors produced by tumor cells or host cells in the tumor microenvironment. Therefore, non-immunogenic tumors cannot elicit an immune response, regardless of the presence of any inhibitory signals sent to immune cells. Non-immunogenic tumors are generally associated with a poor prognosis and are rarely responsive to most treatment strategies.

[0007] Therefore, there is a continuous and urgent need for new anticancer therapies and the identification of new molecules that can enhance the effects of known anticancer treatments. SUMMARY OF THE INVENTION

[0009] The invention is defined by the claims.

[0010] The inventors have shown that specific benzenesulfonamide thiazole compounds have the ability to significantly enhance the effects of anticancer treatments (including chemotherapy, targeted therapy and immunotherapy). Specific benzenesulfonamide thiazole compounds used according to the present invention have been disclosed in an international application published with reference to WO2014 / 07248. They have anticancer properties and target GRP78. Surprisingly, the effects obtained when these compounds are combined with anticancer treatments are significantly higher than the effects obtained when each treatment is used alone.

[0011] The inventors further demonstrated that this combination therapy elicited significant tumor growth inhibition, tumor regression, and better overall survival in patients overexpressing circulating or intratumoral GRP78.

[0012] It has been shown that overexpression of GRP78 is associated with poor prognosis in a variety of cancers, such as ovarian cancer (see Samanta et al. Scientific reports 10.1 (2020): 1-12), melanoma (Shimizu et al. Pathology & Oncology Research 23.1 (2017): 111-116), lung cancer (Xia et al. Journal of Translational Medicine 19.1 (2021): 1-14), gastric cancer (Zhang et al. Clinical & experimental metastasis 23.7 (2006): 401-410), breast cancer (Oncology letters 10.4 (2015): 2149-2155), esophageal cancer (Zhao et al. Digestive diseases and sciences 60.9 (2015): 2690-2699), pancreatic cancer (Tong et al. Pancreatology 21.7 (2021): 1378-1385 or colorectal cancer (Thornton et al. International journal of cancer 133.6 (2013): 1408-1418). The inventors have shown that the combination according to the invention allows a significant reduction in the intratumoral and circulating levels of GRP78 in patients compared to a monotherapy comprising a benzenesulfonamide thiazole compound or said "conventional" anticancer treatment alone.

[0013] Therefore, combination therapies according to the present invention will be particularly beneficial for patients who have high levels of GRP78 and are therefore identified as having a poor prognosis.

[0014] Therefore, the present invention relates to the combination of anticancer therapy with a benzenesulfonamide thiazole compound of formula (I):

[0015]

[0016] in

[0017] Q1 to Q5 are the same or different, indicating CR6

[0018] R1 represents a C6-C containing one or two fused rings 10Aryl, wherein 2 to 5 carbon atoms may be replaced by heteroatoms selected from O, S, N and NR6, and finally 5 to 11 selected from R6, halogen, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2) p- NR6R7, (CH2) p- OR6 and (CH2) P Substituent substitution of SR6,

[0019] R2 is SO2R1 or R6;

[0020] R3 and R4 are the same or different and are selected from COR8 and R6

[0021] R5 represents R6, aryl, OR6, SR6, halogen, CN, NO2, CF3, OCF3, COOR6, SO2NR6R7, CONR6R7, NR6R7 and NHCOR6,

[0022] R6 and R7 are the same or different and represent H or alkyl

[0023] R8 is selected from H, alkyl, cycloalkyl, aryl, alkylaryl, wherein the aryl may be substituted by one to four identical or different R5 substituents,

[0024] Or R8 represents -(CH2) q -NR6R7,

[0025] p represents an integer from 0 to 6,

[0026] q represents an integer from 0 to 6,

[0027] wherein the thiazolyl group is attached to the 6-membered group at the meta or para position relative to the sulfonamide group, and wherein the thiazolyl group is attached to the 6-membered group at the alpha or beta position relative to the S atom,

[0028] For use in treating cancer in patients who have been identified as overexpressing GRP78. DETAILED DESCRIPTION OF THE INVENTION

[0030] Using several cancer mouse models (e.g., colorectal CT26 allograft model) and in vitro cancer cell line models (e.g., melanoma, myeloma, and gastric, pancreatic, colorectal cancer cell lines), the inventors have shown that combination therapy using benzenesulfonamide thiazole compounds and "conventional" anticancer treatments significantly improves survival and strongly reduces tumor growth compared to monotherapy containing either benzenesulfonamide thiazole compounds or the "conventional" anticancer treatments alone. They also showed that mice treated with the combination had significantly reduced levels of circulating and inter-tumor GRP78 compared to vehicle and "conventional" anticancer treatments.

[0031] The present inventors have significantly demonstrated strong synergy between compounds such as immune checkpoint inhibitors and benzenesulfonamide thiazole compounds disclosed herein. Without wishing to be bound by theory, the present inventors propose that the benzenesulfonamide thiazole compounds described herein confer tumor immunogenicity, i.e., can be detected by the immune system, thereby enhancing the anticancer effect of combined anticancer therapy. The present inventors also show that a specific combination of benzenesulfonamide thiazole compounds and anticancer therapy is particularly advantageous in patients who overexpress GRP78.

[0032] Therefore, the present invention represents a very promising therapy for the treatment of cancer.

[0033] Thus, in a first aspect, the present invention relates to a combination of an anticancer treatment with a benzenesulfonamide thiazole of formula (I):

[0034]

[0035] in

[0036] Q1 to Q5 are the same or different, indicating CR6

[0037] R1 represents a C6-C containing one or two fused rings 10 Aryl, wherein 2 to 5 carbon atoms may be replaced by heteroatoms selected from O, S, N and NR6, and finally 5 to 11 selected from R6, halogen, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2) p- NR6R7, (CH2) p- OR6 and (CH2) P Substituent substitution of SR6,

[0038] R2 is SO2R1 or R6;

[0039] R3 and R4 are the same or different and are selected from COR8 and R6

[0040] R5 represents R6, aryl, OR6, SR6, halogen, CN, NO2, CF3, OCF3, COOR6, SO2NR6R7, CONR6R7, NR6R7 and NHCOR6,

[0041] R6 and R7 are the same or different and represent H or alkyl

[0042] R8 is selected from H, alkyl, cycloalkyl, aryl, alkylaryl, wherein the aryl may be substituted by one to four identical or different R5 substituents,

[0043] Or R8 represents -(CH2) q -NR6R7,

[0044] p represents an integer from 0 to 6,

[0045] q represents an integer from 0 to 6,

[0046] wherein the thiazolyl group is attached to the 6-membered group at the meta or para position relative to the sulfonamide group, and wherein the thiazolyl group is attached to the 6-membered group at the alpha or beta position relative to the S atom,

[0047] or, if appropriate, a pharmaceutically acceptable salt thereof and / or an isomer, tautomer, solvate or isotopic variant thereof.

[0048] For use in treating cancer in patients who have been identified as overexpressing GRP78.

[0049] A "combination" for use according to the present invention encompasses both:

[0050] -Anti-cancer treatment / agents for the treatment of cancer, wherein the anti-cancer agent is used in combination with a benzenesulfonamide thiazole of formula (I) as defined above; and

[0051] - A benzenesulfonamide thiazole of formula (I) as defined above for use in the treatment of cancer, wherein the benzenesulfonamide thiazole is used in combination with an anticancer agent.

[0052] A "combination" for use according to the invention also includes a "kit of parts" comprising:

[0053] - anticancer agents; and

[0054] - a compound of formula (I) as defined above,

[0055] For use in treating cancer in patients who have been identified as overexpressing GRP78.

[0056] The term "kit of parts" herein refers to a combined preparation in which the active ingredients are physically separated for combined therapy administered to a patient simultaneously or sequentially. Thus, according to the present invention, the anticancer agent and the compound of formula (I) are administered to a patient in separate forms, simultaneously, separately or sequentially in any order, for the treatment of cancer.

[0057] According to a further embodiment, the present invention also relates to a kit of parts per se, i.e. to a kit of parts comprising:

[0058] - anticancer agents; and

[0059] - a compound of formula (I) as defined above.

[0060] Anti-cancer treatments / agents

[0061] According to the present invention, the anti-cancer treatment is any anti-cancer agent selected from chemotherapy, targeted therapy, immunotherapy and combinations thereof.

[0062] "Chemotherapy", "chemotherapeutic" and "chemotherapeutic agent" refer to compounds that are effective in inhibiting tumor growth. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, ipresulfonic acid and pyresulfonic acid; aziridines such as phendopa, carboquinone, methandopa and uradopa; ethyleneimine and methylimine compounds including hexamethylmelamine, triethylenetriamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylmelamine; acetylated compounds (particularly pyrethrin and pyrethrin ketone); camptothecins (including irinotecan and topotecan); bryostatin; carlistatin; CC-1065 (including its adozoline, kazoline and biszoline synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycins (including synthetic analogs, KW-2189 and CBI-TMI); electroporin; cytochrome; chondroitin; spongestatin; nitrogen mustards such as chlorambucil, naphthyl mustard, cyclophosphamide, estrarnustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, nembixin, phenamic acid, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chloramphenicol, fotemustine, lomustine, nimustine, ranimustine; antibiotics, such as enediyne antibiotics (e.g. calicheamicin, especially calicheamicin 11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl.33:183-186 (1994); dynamin, including dynamin A; epothilones; and the neocarcinogen chromophores and related chromoprotein enediyne antibiotic chromophores, aclarubicin, dactinomycin, doxorubicin, azaserine, bleomycin, actinomycin C, karanomycin, carminomycin, carmophorin, chromomycin, dactinomycin, daunorubicin, detoxorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolinyl-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, vancomycin, mitomycin, mycophenolic acid, nogamycin, oliveromycin, peplomycin, methyl mitomycin, puromycin, triferric doxorubicin, rhodorubicin, streptomycin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as cyclocytidine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calosterone, drostanolone propionate, cyclothiodine, mepiithione, testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglitazone; aldophosphamide Amide glycosides; aminolevulinic acid; amsacrine; amustine; bisantrene; edatrexate; desaminobenzene; demecomycin; diazomequinone; eflornithine; elitrilon; epothilone; epothilone; etoglucose; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine compounds, such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; monoperidinol; azide; pentolstatin; phenacept; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine;. Razoxane; root toxin; sizoran; spirogermanium; tenuisporic acid; triazoquinone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, ellagic acid, pyridoxine A, and pyridoxine); ethyl carbamates; vindesine; dacarbazine; mannomustine; sebromide; dibromodulanol; pipobroman; cytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as paclitaxel ( Bristol-Myers Squibb Oncology, Princeton, N.]) and docetaxel ( Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, carboplatin, oxaliplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; noantor; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and any pharmaceutically acceptable salts, acids or derivatives thereof. Also included within the definition are antihormonal agents used to modulate or inhibit hormonal effects on tumors, such as antiestrogens, including, for example, tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxetine, ketotifen, LY117018, onapristone and toremifene (Falenton); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and any pharmaceutically acceptable salts, acids or derivatives of the foregoing.

[0063] According to a preferred embodiment, the chemotherapeutic agent used in the present invention is selected from doxorubicin, toxoids such as paclitaxel and docetaxel, gemcitabine, antimetabolites such as methotrexate and 5-fluorouracil (5-FU), platinum analogs such as cisplatin and orthoplatin, and camptothecins such as irinotecan and topotecan.

[0064] "Targeted therapy" refers to agents that work by blocking the growth of cancer cells by interfering with specific targeted molecules required for carcinogenesis and tumor growth. Most targeted therapies are small molecule drugs or monoclonal antibodies. It is worth noting that some targeted therapies may qualify as immunotherapeutic agents and / or chemotherapeutic agents. Examples of targeted therapies include bortezomib, Braf inhibitors such as vemurafenib and dabrafenib, cobimetinib, imatinib, gefitinib, erlotinib, sorafenib, sunitinib, dasatinib, lapatinib, nilotinib, tamoxifen, Janus kinase inhibitors such as tofacitinib, ALK inhibitors (such as crizotinib), Bcl-2 inhibitors such as venetoclax, obitutoclax, navitoclax and gossypol, PARP inhibitors such as olaparib, rucaparib, niraparib and talazoparib, PI3K Inhibitors such as pembrolizumab, apatinib, zotarumustine, MEK inhibitors such as trametinib, CDK inhibitors, Hsp90 inhibitors, Hedgehog signaling pathway inhibitors such as vismodegib and sonidegi, salinomycin, VAL-083, Vinatfolide, tansimustine, everomustine, vemurafenib, trametinib, dabrafenib, monoclonal antibodies including pembrolizumab, rituximab, alemtuzumab, cetuximab, panitumumab, bevacizumab and ipilimumab.

[0065] According to a specific embodiment, the targeted therapy used according to the invention is selected from bortezomib, vemurafenib and cobimetinib.

[0066] "Immunotherapy", "immunotherapy" or "immunotherapeutic agent" refers to a compound, composition or treatment that indirectly or directly enhances, stimulates or increases the body's immune response to cancer cells and / or reduces the side effects of other anti-cancer treatments. Therefore, immunotherapy is a therapy that directly or indirectly stimulates or enhances the immune system's response to cancer cells and / or reduces side effects that may be caused by other anti-cancer agents. Immunotherapy is also referred to in the art as immunological therapy, biological therapy, biological response modifier therapy and biological therapy. Examples of commonly used immunotherapeutic agents known in the art include, but are not limited to, cytokines, cancer vaccines, monoclonal antibodies and non-cytokine adjuvants. Alternatively, immunotherapy may include administering a certain amount of immune cells (T cells, NK cells, dendritic cells, B cells...) to the patient.

[0067] Immunotherapeutic agents can be nonspecific, i.e., generally boost the immune system so that the body becomes more effective in fighting the growth and / or spread of cancer cells, or they can be specific, i.e., immunotherapy regimens that target the cancer cells themselves. Nonspecific and specific immunotherapeutic agents can be used in combination.

[0068] Nonspecific immunotherapeutic agents are substances that stimulate or indirectly improve the immune system. Nonspecific immunotherapeutic agents have been used alone as the primary therapy for treating cancer, and in addition to the primary therapy, in this case, nonspecific immunotherapeutic agents act as adjuvants to enhance the effectiveness of other therapies (such as cancer vaccines). Nonspecific immunotherapeutic agents can act on key immune system cells and cause secondary responses, such as increased production of cytokines and immunoglobulins. Alternatively, the reagent itself may include cytokines. Nonspecific immunotherapeutic agents are generally divided into cytokines or non-cytokine adjuvants.

[0069] Many cytokines have found use in cancer treatment as general non-specific immunotherapies designed to boost the immune system or as adjuvants given with other therapies. Suitable cytokines include, but are not limited to, interferons, interleukins, and colony stimulating factors.

[0070] Interferon (IFN) includes common types of IFN, IFN-α, IFN-β and IFN-γ. IFN can act directly on cancer cells, for example, by slowing down their growth, promoting them to develop into cells with more normal behavior and / or increasing their antigen production, so that cancer cells are more easily recognized and destroyed by the immune system. IFN can also act indirectly on cancer cells, for example, by slowing down angiogenesis, strengthening the immune system and / or stimulating natural killer (NK) cells, T cells and macrophages. Recombinant IFN-α can be commercially available as Roferon (Roche Pharmaceuticals) and Intron A (Schering Corporation). IFN-α is used alone or in combination with other immunotherapies or chemotherapy to be shown in the effect of treating various cancers, including melanoma (including metastatic melanoma), renal cancer (including metastatic renal cancer), breast cancer, prostate cancer and cervical cancer (including metastatic cervical cancer).

[0071] Interleukins include IL-2, IL-4, IL-11 and IL-12. Examples of commercially available recombinant interleukins include (IL-2; Chiron Corporation) and (IL-12; Wyeth Pharmaceuticals). Interleukins alone or in combination with other immunotherapeutic or chemotherapeutic agents have shown efficacy in the treatment of various cancers, including renal cancer (including metastatic renal cancer), melanoma (including metastatic melanoma), ovarian cancer (including recurrent ovarian cancer), cervical cancer (including metastatic cervical cancer), breast cancer, colorectal cancer, lung cancer, brain cancer, and prostate cancer.

[0072] Colony stimulating factors (CSF) include granulocyte colony stimulating factor (G-CSF or filgrastim), granulocyte-macrophage colony stimulating factor (GM-CSF or sargramostim) and erythropoietin (epoetin alfa, darbepoetin α). Various recombinant colony stimulating factors are commercially available, for example, (G-CSF; Amgen), Neulasta (pelfilgrastim; Amgen), Leukine (GM-CSF; Berlex), Procrit (erythropoietin; OrthoBiotech), Epogen (erythropoietin; Amgen), Arnesp (erythropoietin). Colony stimulating factors have demonstrated efficacy in the treatment of cancers including melanoma, colorectal cancer (including metastatic colorectal cancer), and lung cancer.

[0073] Non-cytokine adjuvants suitable for the combination of the present invention include, but are not limited to, levamisole, aluminum hydroxide (alum), Bacillus Calmette-Guérin (ACG), incomplete Freund's adjuvant (IFA), QS-21, DETOX, hemocyanin (KLH) and dinitrophenyl (DNP). Combinations of non-cytokine adjuvants with other immunological and / or chemotherapeutic agents have been shown to be effective against various cancers, including, for example, colon and colorectal cancer (levamisole); melanoma (BCG and QS-21); renal and bladder cancer (BCG).

[0074] In addition to having specific or nonspecific targets, immunotherapeutics can be active, stimulating the body's own immune response, or they can be passive, involving components of the immune system generated outside the body.

[0075] Active specific immunotherapy often involves the use of cancer vaccines. Cancer vaccines containing whole cancer cells, parts of cancer cells, or one or more antigens derived from cancer cells have been developed. Cancer vaccines, alone or in combination with one or more immune or chemotherapeutic agents, are being studied to treat several types of cancer, including melanoma, renal cancer, ovarian cancer, breast cancer, colorectal cancer, and lung cancer.

[0076] Immunotherapy can consist of adoptive immunotherapy as described by Nicholas P. Restifo, Mark E. Dudley and Steven A. Rosenberg "Adoptive immunotherapy for cancer: harnessing the T cell response, Nature Reviews Immunology, Volume 12, April 2012. In adoptive immunotherapy, the patient's circulating lymphocytes or tumor-infiltrating lymphocytes are isolated in vitro, activated by lymphokines such as IL-2 or infiltrated with tumor necrosis genes, and re-administered (Rosenberg et al., 1988; 1989). The activated lymphocytes are most preferably the patient's own cells, which were previously isolated from blood or tumor samples and activated (or "expanded") in vitro. This form of immunotherapy has resulted in several cases of regression of melanoma and renal cancer.

[0077] Passive specific immunotherapy generally involves the use of one or more monoclonal antibodies that are specific for a particular antigen found on the surface of cancer cells or that are specific for a particular cell growth factor. Monoclonal antibodies can be used to treat cancer in a variety of ways, for example, to enhance a subject's immune response to a particular type of cancer, to interfere with the growth of cancer cells by targeting specific cell growth factors (such as those involved in angiogenesis), or by enhancing the delivery of other anti-cancer agents to cancer cells when linked or conjugated to agents such as chemotherapeutic agents, radioactive particles, or toxins.

[0078] Monoclonal antibodies currently used as cancer immunotherapeutics suitable for inclusion in the combinations of the present invention include, but are not limited to, rituximab ( ), trastuzumab ( )、Ibrutinib ( )、Tositumomab( ), Cetuximab (C-225, ), bevacizumab ( ), Gemtuzumab ozogamicin ( ), Alemtuzumab ( ) and BL22. Monoclonal antibodies are used to treat a variety of cancers, including breast cancer (including advanced metastatic breast cancer), colorectal cancer (including advanced and / or metastatic colorectal cancer), ovarian cancer, lung cancer, prostate cancer, cervical cancer, melanoma and brain tumors. Other examples include immune checkpoint inhibitors.

[0079] Expression "immune checkpoint protein" is widely known in the art, and refers to molecules expressed by T cells, and it either turns up the signal (stimulatory checkpoint molecule) or turns down the signal (inhibitory checkpoint molecule). Immune checkpoints constitute immune checkpoint pathways, such as CTLA-4 and PD-1 dependent pathways (see, e.g., Pardoll, 2012.Nature RevCancer 12:252-264; Mellman et al., 2011.Nature 480:480-489). Examples of inhibitory checkpoint molecules include A2AR, B7-H3, B7-H4, BTLA, CTLA-4, CD277, IDO1, KIR, PD-1, LAG-3, TIM-3TIGIT and VISTA.

[0080] A2AR (“adenosine A2A receptor”) is considered an important checkpoint in cancer therapy: the presence of adenosine in the immune microenvironment leads to activation of the A2a receptor and induces a negative immune feedback loop and the tumor microenvironment has a relatively high concentration of adenosine. B7-H3, also known as CD276, was originally understood to be a co-stimulatory molecule, but is now considered a co-inhibitory molecule. B7-H4, also known as VTCN1, is expressed by tumor cells and tumor-associated macrophages and is involved in tumor escape. BTLA (“B and T lymphocyte attenuator”), also known as CD272, has HVEM (herpes virus entry mediator) as its ligand. BTLA is expressed on the surface of human CD8 + Down-regulated during differentiation of T cells from naive to effector phenotype. Tumor-specific human CD8 +T cells express high levels of BTLA. Expression of CTLA-4 (“cytotoxic T lymphocyte-associated protein 4”), also known as CD152, on Treg cells controls T cell proliferation. IDO1 (“indoleamine 2,3-dioxygenase 1”) is a tryptophan catabolizing enzyme - an enzyme associated with immunosuppression. IDO1 is known to inhibit T and NK cells, generate and activate Treg and myeloid-derived suppressor cells, and promote tumor angiogenesis. KIR (“killer cell immunoglobulin-like receptor”) is a receptor for MHC class I molecules on natural killer cells. LAG3 (“lymphocyte activation gene-3”) inhibits Tregs and CD8 + The immune response is suppressed by direct inhibition of T cells. The PD-1 ("programmed death 1") receptor has two ligands, PD-L1 and PD-L2. This checkpoint is the target of Merck's commercialized pembrolizumab. Targeting PD-1 allows the restoration of immune function in the tumor microenvironment. TIM-3 ("T cell immunoglobulin domain and mucin domain 3") is a key target of activated human CD4 + T cells express and regulate Th1 and Th17 cytokines. TIM-3 acts as a negative regulator of Th1 / Tc1 function by triggering cell death when interacting with its ligand galectin-9. VISTA ("V-domain Ig inhibitor of T cell activation") is mainly expressed on hematopoietic cells. The consistent expression of VISTA on intratumoral leukocytes allows VISTA blockade to be effective in a wide range of solid tumors. TIGIT ("T cell immune receptor with Ig and ITIM domains") is an immune receptor present on a certain percentage of T cells and natural killer cells (NK). TIGIT inhibits T cell activation in vivo.

[0081] "Immune checkpoint inhibitors" or "checkpoint blocking cancer immunotherapeutics" have their general meaning in the art and refer to any compound that inhibits the function of an immunosuppressive checkpoint protein. Inhibition includes both reduced function and complete blockade. Immune checkpoint inhibitors include peptides, antibodies, nucleic acid molecules, and small molecules. Preferred immune checkpoint inhibitors are antibodies that specifically recognize immune checkpoint proteins. Administration of the immune checkpoint inhibitors used in the present invention is used to enhance CD8 + T cell proliferation, migration, persistence and / or cytotoxic activity. CD8 + T cells are a subset of T cells that express CD8 on their surface. They are MHC class I restricted and function as cytotoxic T cells. They are also known as cytotoxic T lymphocytes (CTLs), T-killer cells, cytolytic T cells, CD8 +T cells or killer T cells. The CD8 antigen is a member of the immunoglobulin supergene family and is an associative recognition element in the major histocompatibility complex class I-restricted interaction. Immune checkpoint inhibitors enhance CD8 + The ability of T cells to kill can be determined by any assay known in the art. Typically, the assay is an in vitro assay in which CD8 + T cells and target cells (such as CD8 + For example, the immune checkpoint inhibitors of the present invention can be directed against the increase of CD8 + T cells are selected for their ability to specifically lyse by more than about 20%, preferably at least about 30%, at least about 40%, at least about 50% or more. Examples of protocols for classical cytotoxicity assays are routine.

[0082] In general, immune checkpoint inhibitors are agents that block immunoinhibitory receptors expressed by activated T lymphocytes (e.g., cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PDCD1, also known as PD-1)) or NK cells (e.g., various members of the killer cell immunoglobulin-like receptor (KIR) family), or agents that block the primary ligands of these receptors, such as the PD-1 ligand CD274 (most commonly known as PD-L1 or B7-H1).

[0083] Typically, checkpoint blockade cancer immunotherapeutics are antibodies.

[0084] In some embodiments, the checkpoint blockade cancer immunotherapeutic is an antibody selected from the group consisting of anti-PD1 antibody, anti-PDL1 antibody, anti-PDL2 antibody, anti-CTLA4 antibody, anti-TIM-3 antibody, anti-LAG3 antibody, anti-IDO1 antibody, anti-TIGIT antibody, anti-B7H3 antibody, anti-B7H4 antibody, anti-BTLA antibody, and anti-B7H6 antibody.

[0085] Examples of anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies are described in U.S. Pat. Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149 and PCT Published Patent Application Nos.: WO 03042402, WO 2008156712, WO2010089411, WO 2010036959, WO 2011066342, WO 2011159877, WO 2011082400 and WO2011161699. In some embodiments, the PD-1 blocker includes an anti-PD-L1 antibody (e.g., atezolizumab, avelumab or durvalumab). In other embodiments, the PD-1 blocker includes an anti-PD-L2 antibody. In certain other embodiments, PD-1 blockers include anti-PD-1 antibodies and similar binding proteins, such as nivolumab (MDX1106, BMS936558, ONO4538), a fully human IgG4 antibody that binds to and blocks the activation of PD-1 through its ligands PD-L1 and PD-L2; lencanezumab (MK-3475 or SCH 900475), a humanized monoclonal IgG4 antibody against PD-1; CT-011 is a humanized antibody that binds to PD-1; AMP-224 is a fusion protein of B7-DC; antibody Fc portion; BMS-936559 (MDX-1105-01) is used for PD-L1 (B7-H1) blockade.

[0086] Examples of anti-CTLA-4 antibodies are described in U.S. Pat. Nos. 811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; ​​6,682,736; 6,984,720; and 7,605,238. One anti-CDLA-4 antibody is tremelimumab (tesimumab, CP-675,206). In some embodiments, the anti-CTLA-4 antibody is ipilimumab (also known as 10D1, MDX-D010), a fully human monoclonal IgG antibody that binds to CTLA-4.

[0087] Other immune checkpoint inhibitors include lymphocyte activation gene-3 (LAG-3) inhibitors, such as IMP321, a soluble Ig fusion protein (Brignone et al., 2007, J. Immunol. 179:4202-4211).

[0088] Other immune checkpoint inhibitors include B7 inhibitors, such as B7-H3 and B7-H4 inhibitors, in particular, the anti-B7-H3 antibody MGA271 (Loo et al., 2012, Clin. Cancer Res. July 15 (18) 3834).

[0089] Also included are TIM3 ("T-cell immunoglobulin domain and mucin domain 3") inhibitors (Fourcade et al., 2010, J. Exp. Med. 207: 2175-86 and Sakuishi et al., 2010, J. Exp. Med. 207: 2187-94). The natural ligand of TIM-3 is galectin 9 (Gal9). Therefore, the term "TIM-3 inhibitor" used herein refers to a compound, substance or composition that can inhibit the function of TIM-3. For example, the inhibitor can inhibit the expression or activity of TIM-3, regulate or block the TIM-3 signaling pathway and / or block the binding of TIM-3 to galectin-9. Antibodies specific for TIM-3 are well known in the art and are generally those described in WO 2011155607, WO 2013006490 and WO 2010117057.

[0090] In some embodiments, the immune checkpoint inhibitor is an indoleamine 2,3-dioxygenase (IDO) inhibitor, preferably an IDO1 inhibitor. Examples of IDO inhibitors are described in WO 2014150677. Examples of IDO inhibitors include, but are not limited to, 1-methyltryptophan (IMT), β-(3-benzofuranyl)-alanine, β-(3-benzo(b)thienyl)-alanine), 6-nitrotryptophan, 6-fluorotryptophan, 4-methyltryptophan, 5-methyltryptophan, 6-methyltryptophan, 5-methoxytryptophan, 5-hydroxytryptophan, indole 3-methanol, 3,3'-diindolylmethane, epigallocatechin gallate, 5-bromo-4-chloro-indoxyl 1,3-diacetate, 9-vinylcarbazole, acemetacin, 5-bromotryptophan, 5-bromoindoxyl diacetate, 3-aminonaphthoic acid, pyrrolidine dithiocarbamate, 4-phenylimidazole, a brassinolide derivative, a thiohydantoin derivative, a β-carboline derivative, or a brassinolide derivative. Preferably, the IDO inhibitor is selected from 1-methyl-tryptophan, β-(3-benzofuranyl)-alanine, 6-nitro-L-tryptophan, 3-amino-naphthoic acid and β-[3-benzo(b)thienyl]-alanine or a derivative or prodrug thereof.

[0091] In some embodiments, the immune checkpoint inhibitor is an anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody.

[0092] According to a specific embodiment, the anti-cancer treatment according to the invention is an immune checkpoint inhibitor, preferably selected from anti-PD-1 antibodies and anti-PD-L1 antibodies.

[0093] In a preferred embodiment, the checkpoint blockade cancer immunotherapeutic agent is a PD-1 blocking antibody, such as nivolumab or pembrolizumab.

[0094] Compounds of formula (I)

[0095] The benzenesulfonamide thiazole compound of formula (I) used in the present invention has been extensively disclosed and studied in the international patent application published with reference to WO2014 / 072486, the contents of which are incorporated herein by reference in their entirety.

[0096] According to a preferred embodiment, the compounds of formula (I) used in the present invention also belong to formula (II):

[0097]

[0098] wherein Q1 to Q5, R2, R3, R4 and R5 are as defined above, and R9 represents R6, halogen, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2) p- NR6R7, (CH2) p- OR6 and (CH2) P SR6.

[0099] wherein R6, R7 and p are as defined above, n represents 1, 2, 3 or 4, and the naphthyl group is attached to the sulfur atom at the 1, 2 or 3 position relative to the quaternary carbon.

[0100] In the above formula (I) or (II):

[0101] -R2 preferably represents H,

[0102] -R3 preferably represents H,

[0103] -R4 is preferably CO-alkyl,

[0104] -R6 is preferably H or alkyl,

[0105] -R9 is preferably NR6R7, wherein R6 and R7 both preferably represent CH3,

[0106] The -thiazolyl group is preferably attached to the 6-membered aromatic ring in the meta position relative to the sulfonamide group and also preferably in the β-position relative to the sulfur atom.

[0107] In the above formulae (I) and (II), alkyl represents a straight-chain or branched group containing 1, 2, 3, 4 or 5 carbon atoms. This also applies if they carry substituents or occur as substituents of other groups, for example in O-alkyl, S-alkyl, etc. Examples of suitable alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0108] Cycloalkyl groups contain 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0109] Aryl denotes an aromatic carbocyclic ring containing 6 to 10 carbon atoms.

[0110] Finally, halogen denotes a halogen atom selected from fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

[0111] Preferably, in formula (I) and (II), the free bond on the phenyl group means that the phenyl group can be substituted at the meta position or the para position.

[0112] Preferred compounds according to the invention are:

[0113] N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)acetamide

[0114] 5-(Dimethylamino)-N-(3-(2-(methylamino)thiazol-4-yl)phenyl)naphthalene-1-sulfonamide

[0115] N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)-4-methylbenzamide

[0116] N-(3-(2-aminothiazol-4-yl)phenyl)-5-(dimethylamino)naphthalene-1-sulfonamide

[0117] N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)benzamide

[0118] N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)trimethylacetamide

[0119] 2-Fluoro-N-(3-(2-(methylamino)thiazol-4-yl)phenyl)benzenesulfonamide

[0120] N-(4-(4-(Naphthalene-2-sulfonylamino)phenyl)thiazol-2-yl)acetamide

[0121] N-(4-(4-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)acetamide

[0122] N-(4-(4-(2-Fluorophenylsulfonylamino)phenyl)thiazol-2-yl)acetamide

[0123] N-(4-(4-(2,4-difluorophenylsulfonylamino)phenyl)thiazol-2-yl)acetamide

[0124] N-(4-(4-(3-(trifluoromethyl)benzenesulfonylamino)phenyl)thiazol-2-yl)acetamide

[0125] N-(4-(3-(3-(trifluoromethyl)benzenesulfonylamino)phenyl)thiazol-2-yl)acetamide

[0126] N-(4-(4-(trifluoromethyl)benzenesulfonylamino)phenyl)thiazol-2-yl)acetamide

[0127] N-(4-(3-(4-methylphenylsulfonylamino)phenyl)thiazol-2-yl)acetamide

[0128] N-(4-(3-(2-Nitrophenylsulfonylamino)phenyl)thiazol-2-yl)acetamide

[0129] N-(4-(3-(3-Nitrophenylsulfonylamino)phenyl)thiazol-2-yl)acetamide

[0130] N-(4-(3-(phenylsulfonylamino)phenyl)thiazol-2-yl)acetamide

[0131] N-(4-(3-(Methylsulfonylamino)phenyl)thiazol-2-yl)acetamide

[0132] N-(4-(4-(4-Methylphenylsulfonylamino)phenyl)thiazol-2-yl)acetamide

[0133] as well as

[0134] N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)-6-aminohexanamide.

[0135] According to a more preferred embodiment, the benzenesulfonamide thiazole compound of formula I used in the present invention corresponds to formula (III):

[0136]

[0137] The compound of formula (III) is also referred to as compound "HA15" in the present invention.

[0138] Processes for the synthesis of benzenesulfonamide thiazole compounds useful according to the invention are disclosed in the above-mentioned application WO 2014 / 072486.

[0139] The benzenesulfonamide thiazole compounds of formula (I), (II) and (III) may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include acid addition salts and base salts thereof.

[0140] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, toluenesulfonate and trifluoroacetate and xinafoate.

[0141] Suitable alkaline salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemi-salts of acids and bases, such as hemisulphates and hemicalcium salts, can also be formed. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0142] The benzsulfonamide thiazole compound used in the present invention can exist in non-solvated and solvated forms. The term "solvate" describes a molecular complex comprising a benzsulfonamide thiazole compound and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. Complexes such as inclusion compounds, drug-host inclusion complexes are also included, wherein, in contrast to the above-mentioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Drug complexes containing two or more organic and / or inorganic components are also included, which can be stoichiometric or non-stoichiometric amounts. The resulting complex can be ionized, partially ionized or non-ionized. For a review of this complex, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[0143] Therefore, the benzenesulfonamide thiazole compound of formula (I) includes its salt, solvate and complex and the solvate and complex of its salt. The benzenesulfonamide thiazole compound of formula (I) includes all its polymorphs and crystal habits, its prodrugs and isomers (including optical isomers, geometric isomers and tautomers) and isotope-labeled compounds of formula (I).

[0144] Therapeutic Uses

[0145] As described above, the anti-cancer treatments and benzenesulfonamide thiazole compounds according to the present invention are useful for treating cancer in a patient.

[0146] Accordingly, the present disclosure provides a method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of an anti-cancer therapy and a benzenesulfonamide thiazole as defined above.

[0147] According to the present invention, anticancer therapy and benzenesulfonamide thiazole compound are administered to the patient simultaneously, separately or in any order. According to a specific embodiment, anticancer therapy is administered after the benzenesulfonamide thiazole compound is administered. In other words, anticancer therapy is administered to patients who have received benzenesulfonamide thiazole compound. According to another specific embodiment, benzenesulfonamide thiazole compound is administered after anticancer therapy. In other words, benzenesulfonamide thiazole compound is administered to patients who have received immune checkpoint inhibitors.

[0148] The terms "subject" and "patient" refer to a human or animal suffering from cancer. Typically the patient is a mammal. The patient can be, for example, a human, a feline such as a cat, a canine such as a dog, or an equine such as a horse. Preferably, the patient is a human.

[0149] The patient according to the present invention overexpresses GRP78.

[0150] "78 kDa glucose-regulated protein" or "GRP78", also known as "binding immunoglobulin protein" (BiP) or "heat shock 70 kDa protein 5" (HSPA5), is a protein encoded by the HSPA5 gene in humans. It is an endoplasmic reticulum protein chaperone that plays a key role in protein folding and quality control within the lumen of the endoplasmic reticulum. The sequence of GRP78 can be found in the Uniprot database at reference P11021.

[0151] "Overexpression" refers to the level of GRP78 measured in a biological sample obtained from a patient that is significantly higher than the level measured in a control sample. Typically, the control sample can be a sample obtained from a control population or a control tissue. The control population is usually composed of healthy subjects, i.e., subjects who do not suffer from cancer or any other disease. The control tissue is usually composed of healthy tissue, i.e., tissue that is not affected by the disease. The control tissue is usually obtained from the patient himself. Those skilled in the art know several techniques that allow determination of whether a gene / protein is overexpressed compared to a control sample. Those skilled in the art are familiar with these techniques used routinely. Several studies on the evaluation of GRP78 levels have been published (see, e.g., Huang et al (2018). International Journal of Clinical and Experimental Pathology, 11 (11), 5223). Typically, when the level of GRP78 is 1.5 times higher than the level measured in the control population, preferably 1.7 times higher, and more preferably 2 times higher, the level of GRP78 is considered to be "overexpressed".

[0152] Typically, the GRP78 levels measured are circulating GRP78 levels or intratumoral GRP78 levels.

[0153] "Circulating GRP78" refers to the GRP78 protein present in the patient's blood circulation, usually in the cell-free portion of the patient's blood (plasma / serum). The level of circulating GRP78 protein is usually measured by assessing the amount of GRP78 in a blood sample (usually a plasma / serum sample obtained from a patient). The control for determining whether the circulating GRP78 level is overexpressed is usually the GRP78 level measured in a blood sample from a control population.

[0154] "Intratumoral GRP78" refers to GRP78 protein expressed in a patient's tumor. The level of GRP78 protein is usually measured by assessing the amount of GRP78 expressed in a tumor sample (usually a tumor biopsy obtained from a patient). The control for determining whether intratumoral GRP78 levels are overexpressed is usually the GRP78 level measured in a control tissue, i.e., a healthy tissue from a patient.

[0155] Those skilled in the art are familiar with the many techniques used daily to determine the expression levels of proteins such as GRP78.

[0156] These methods generally involve contacting the biological sample to be analyzed with a reagent that is capable of specifically binding to the target protein. The reagent is typically a polyclonal or monoclonal antibody. The presence of the protein is then detected by standard immunoassay methods, usually after separation of the protein by electrophoresis (a technique also known as "Western blotting") or by immunoassays using direct, indirect, competitive or immune capture methods (a technique also known as "ELISA"). The formation of a complex between the target protein and the antibody targeting the protein is usually detected and quantified by measuring an enzyme reaction that produces a colored, chemiluminescent or fluorescent product, resulting in a specific staining pattern with a staining percentage. Typically, "strong staining" is defined as 50% of tumor cells staining positive, "moderate staining" is defined as 10% to <50% of tumor cells staining positive, and "weak staining" is defined as <10% of tumor cells staining positive (Samanta et al, 2022).

[0157] Several kits are currently available for determining plasma / serum levels of GRP78. For example, an ELISA kit referenced ADI-900-214 commercialized by Enzo Life Sciences may be used.

[0158] The level of intratumoral GRP78 can also be determined by measuring the density of cells expressing GRP78. Generally, the method for measuring the density of cells expressing GRP78 includes the step of contacting a tumor tissue sample with at least one selective binding agent that can selectively interact with GRP78. The selective binding agent can be a polyclonal antibody or a monoclonal antibody, an antibody fragment, a synthetic antibody, or other protein-specific reagents such as nucleic acid or peptide aptamers. The technician knows several antibodies specific for GRP78. Many of these antibodies are commercially available. Immunohistochemistry is particularly suitable for evaluating the density of GRP78 cells. Generally, the tissue tumor sample is first incubated with a labeled antibody against GRP78. After washing, the labeled antibody bound to GRP78 is displayed by an appropriate technique, depending on the type of label carried by the labeled antibody, such as radioactive, fluorescent or enzyme labeling.

[0159] The level of GRP78 can also be measured by measuring the amount of mRNA produced by the HSPA5 gene. Methods for measuring the amount of mRNA are well known in the art. For example, nucleic acids contained in the sample are first extracted according to standard methods, such as using a lyase or chemical solution, or extracted by a nucleic acid binding resin according to the manufacturer's instructions. The extracted mRNA is then detected by hybridization (e.g., Northern immunoblot analysis) and / or amplification (e.g., RT-PCR). Quantitative or semi-quantitative RT-PCR is a preferred method.

[0160] Thus, according to a specific embodiment, the present disclosure provides a method for treating cancer in a patient, comprising the step of measuring the level of GRP78 in a tumor or blood / plasma / serum sample obtained from the patient, and if the patient is identified as overexpressing GRP78, administering a therapeutically effective amount of an anti-cancer therapy and a benzenesulfonamide thiazole as defined above.

[0161] For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment. "Treatment" is intended to reverse, alleviate, inhibit the progression of, or prevent one or more symptoms of a disorder or condition to which the term applies, or to reverse, alleviate, inhibit the progression of, or prevent one or more symptoms of a disorder or condition to which the term applies.

[0162] The term "cancer" herein refers to a physiological condition characterized by unregulated or unregulated cell growth or death in a subject. The term "cancer" includes solid tumors and blood-borne tumors.

[0163] In general, the combinations used according to the invention are applicable to various organs of cancer origin (e.g. breast, colon, stomach, rectum, pancreas, lung, skin, head and neck, bladder, ovary, prostate), and also to various cancer cell types (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, melanoma, etc.).

[0164] In a specific embodiment, the patient has a solid cancer selected from the group consisting of skin cancer (e.g., melanoma, non-melanoma skin cancer), colorectal cancer, adrenocortical carcinoma, anal cancer, bile duct cancer (e.g., perihepatic carcinoma, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, bone cancer (e.g., osteoblastoma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma), sarcomas such as liposarcoma and soft tissue sarcoma, brain and central nervous system cancer (e.g., meningioma, astrocytoma, oligodendroglioma, ependymoma, glioma, medulloblastoma, ganglioglioma, schwannoma, germ cell tumor, craniopharyngioma), breast cancer (e.g., ductal carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, lobular carcinoma in situ), cervical cancer, endometrial cancer (e.g., endometrial adenocarcinoma, adenocarcinoma, papillary serous adenocarcinoma), esophageal cancer, gallbladder cancer (mucinous nasopharyngeal carcinoma, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, gastric cancer, testicular cancer (e.g., seminoma, non-seminoma germ cell cancer), thymic cancer, thyroid cancer (e.g., follicular carcinoma, anaplastic carcinoma, dysdifferentiated carcinoma, medullary thyroid cancer), vaginal cancer, vulvar cancer, and uterine cancer (e.g., uterine leiomyosarcoma).

[0165] In a specific embodiment, the patient has a blood cancer, such as leukemia, lymphoma (eg, Hodgkin's lymphoma or non-Hodgkin's lymphoma), and myeloma.

[0166] The benzenesulfonamide thiazole compounds according to the present invention have been shown to be highly effective in sensitizing and resistant cancer cell lines from melanoma, pancreatic cancer and chronic myeloid leukemia (see Millet et al., Journal of medicinalchemistry 59.18 (2016): 8276-8292). Therefore, according to another specific embodiment, the cancer treated according to the present invention is selected from skin cancer, pancreatic cancer and leukemia.

[0167] According to a preferred embodiment, the cancer treated according to the invention is colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, lung cancer or skin cancer (preferably melanoma).

[0168] According to a specific embodiment, the cancer according to the present invention is a non-immunogenic tumor. "Non-immunogenic tumor" refers to a tumor that does not elicit a T cell response in this article. Those skilled in the art are familiar with this concept and know how to determine whether a tumor is immunogenic (see, for example, Wang et al. Elife 8 (2019): e49020). Such tumors are generally associated with:

[0169] - few infiltrating lymphocytes, thus with a low density of infiltrating lymphocytes at the edge or in the center of the tumor, as described, for example, in the international application published under reference WO 2007 / 045996 or according to Determination;

[0170] -CD8 + The exhausted population of T cells is also called "Tex cells" (see Wherry, E. John, and Makoto Kurachi, Nature Reviews Immunology 15.8 (2015): 486-499), which can be identified as shown in Bengsch et al. Immunity 48.5 (2018): 1029-1045.

[0171] - Limited tumor antigen presentation (as shown in Wang (2019));

[0172] - a majority of M2 macrophages and myeloid-derived suppressor cells; and / or

[0173] -Type 2 inflamed tumor microenvironment (see, for example, Gajewski et al. Tumor immune microenvironment in cancer progression and cancer therapy (2017): 19-31 or Trujillo et al. Cancer immunology research 6.9 (2018): 990-1000).

[0174] According to another embodiment, the cancer according to the present invention is "resistant" to immunotherapy, meaning that the patient has little or no response to immunotherapy, and in particular to immune checkpoint inhibitor monotherapy.

[0175] As used herein, the term "responder" refers to a patient who will achieve a response, i.e., a patient whose cancer is eradicated, reduced, or stabilized after treatment. Non-responders or refractory patients include patients whose cancer does not show reduction or stabilization after immunotherapy, particularly after immune checkpoint therapy.

[0176] The compounds used in the present invention can be administered by any suitable route. The skilled person knows which route of administration to use and the corresponding dosage. The compounds useful in the present invention are usually administered parenterally (e.g., intravenously, intramuscularly or subcutaneously) or by oral administration.

[0177] The present invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted as limiting the scope of the present invention in any way. BRIEF DESCRIPTION OF THE DRAWINGS

[0178] Figure 1: CT26 cells (5.10 4 ) were injected subcutaneously into Balb / C mice. Once the tumors reached 50 mm 3 Mice were randomly assigned to different experimental groups and treated daily (ip) with vehicle or HA15 (35 mg / kg) and twice a week with anti-PD1 (6.25 mg / kg) or PBS during two weeks. A: Individual tumor growth curves. B: Survival curves. When the tumor of the mice reached 800 mm 3 The animals were euthanized at 4 ℃ and 7 ℃. The log-rang (Mantel Cox) test was performed to statistically compare the survival rates of different experimental groups. Ns = non-significant, *: p ≤ 0.05, **: P ≤ 0.01, ***: p ≤ 0.001.

[0179] Figure 2 : HA15 induces the expression of CHOP and IFNg in mouse tumors in vivo: Tumors were harvested from mice after HA15 treatment and crushed into lysis buffer to obtain protein lysates. (A) Tumor lysates were analyzed by western immunoblotting with CHOP, IFNγ and HSP90 antibodies. The radiographs provided here were then densitometry analyzed by the ImageJ (Fiji) program. The signal intensity of the target protein was weighted by the signal intensity of the HSP90 control. (B) Intratumoral IFN-γ was quantified in the lysate by a mouse IFN-g ELISA kit. Mann-Whitney test was performed to statistically compare protein expression in two different groups.

[0180] Figure 3 : Graph showing changes in intratumoral GRP78 levels measured in mice treated with combination therapy according to the present invention compared to monotherapy comprising HA15 (BPR001) or anti-PDL1 alone. Example

[0181] Example 1: Combination of HA15 and anti-PD1 antibody in CT26 tumor model

[0182] Materials and methods:

[0183] CT26 allogeneic transplantation experiment

[0184] Five-week-old female BALB / cOlaHsd mice were obtained from Envigo Laboratories. One week later, these mice were subcutaneously inoculated with CT26 cells (5 × 10 5 cells / mouse). Once the tumor reaches 50 mm 3 , each mouse was assigned to a different experimental group (7 mice / group) according to a randomization table created with the "Graphpad Quickcalcs" tool. Thereafter, the animals received intraperitoneal injections of DMA / Tween80 / Labrafil (9 / 1 / 90) + PBS [control group], HA15 in Labrafil (0.7 mg / mouse / day) + PBS [HA15 group], anti-PD1 in PBS (InvivoMAb anti-mouse PD1 (CD279) antibody / Catalog BE0146 / clone: ​​RPM1-14) (0.125 mg / mouse injected 4 times on days 1, 4, 8 and 11 of treatment) + Labrafil [anti-PD1 group] or a combination of HA15 and anti-PD1 treatment [HA15+anti-PD1 group]. Using the equation volume = (length × (width) 2 ) / 2 to measure the tumor volume. When the tumor reaches 800mm 3 At 1 pm, mice were anesthetized by injection of ketamine (100 mg / kg) / xylasine (10 mg / kg) to obtain retro-orbital blood samples. Mice were sacrificed by cervical dislocation, and lymph nodes and tumors were collected for western immunoblotting and ELISA experiments.

[0185] Survival curve shows that the tumor reaches 800mm 3 The percentage of mice with death events over time. A log-rang (Mantel Cox) test was performed to statistically compare the survival rates of different experimental groups. Ns = non-significant, *: p ≤ 0.05, **: P ≤ 0.01, ***: P ≤ 0.001

[0186] Intratumor protein analysis was performed by Western immunoblotting and ELISA.

[0187] In the presence of protein lysis buffer containing 50mmol / l Tris-HCl (pH7.5), 15mmol / l, NaCl, 1% TritonX-100 and 1X protease and phosphatase inhibitors, the tumor mass was crushed into a CK mixing tube (#P 000918-LYSK0, Bertin Technologies) by a "Precellys 24 tissue homogenizer". The tumor lysate was then centrifuged to remove cell debris.

[0188] For western immunoblotting, tumor lysates were prepared in Laemmli buffer. Briefly, tumor lysates (30 μg) were separated by SDS-PAGE, transferred to polyvinylidene difluoride membranes (Millipore), and then exposed to appropriate antibodies. Antibodies against IFN-γ were purchased from Abcam (ab133566). Proteins were visualized using the ECL system from Amersham. The western immunoblot analysis shown is representative of at least three independent experiments.

[0189] Intratumoral IFN-γ was quantified in the same lysate by a mouse interferon-g ELISA kit from Cusabio (#CSB-E04578m). Briefly, 75 μg of tumor lysate (or standard sample) was added to a plate pre-coated with an IFN-γ-specific antibody. After removing any unbound material, a biotin-conjugated antibody specific for IFN-γ was added to the wells. Then, after incubation with avidin-coupled horseradish peroxidase (HRP), the substrate solution was added. Color development is proportional to the amount of IFN-γ bound in the initial step. Statistical analysis was performed by Mann-Whitney test. Ns = non-significant, *: p≤0.05, **: P≤0.01, ***: P≤0.001

[0190] Serum protein analysis by ELISA.

[0191] Mouse blood (500 μL) was placed directly on a tube containing a coagulation activator (Microvette 500ZGel #20-1344, Sarstedt) and centrifuged at 10000 g for 5 minutes to collect serum. Serum IFN-γ was quantified in these samples (100 μL) by the mouse interferon-g ELISA kit from Cusabio (#CSB-E04578m) as described above. Statistical analysis was performed by Mann-Whitney test. Ns = non-significant, *: p ≤ 0.05, **: P ≤ 0.01, ***: p ≤ 0.001.

[0192] result:

[0193] As shown in Figure 1, combination therapy using HA15 and anti-PD-1 antibody significantly improved survival and reduced tumor growth in a mouse syngeneic immune-competent model of colorectal cancer compared to single HA15 (14% complete response) or single anti-PD-1 (33% complete response) antibody treatment. The combination of HA15 and anti-PD-1 immunotherapy (anti-PD-1) resulted in 100% survival at 40 days.

[0194] The present inventors further demonstrated that HA15 induced CHOP and IFNγ expression in CT26 tumors (see Figure 2), indicating an effect mediated by ER (endoplasmic reticulum) stress regulation. This means that HA15 is able to reactivate CD8 through its mode of action and subsequent IFNγ release + T cell lymphocytes.

[0195] The present inventors have further demonstrated that the immune stimulation is localized to the tumor and does not affect the liver, where no changes in the expression of CHOP or IFNγ were observed after HA15 treatment (data not shown).

[0196] These results suggest that HA15 can enhance anti-PD1 responses. These results also suggest that HA15 can be used to convert non-immunogenic tumors into immunogenic tumors that are sensitive to treatment with, for example, immune checkpoint inhibitors.

[0197] Example 2: Combination of HA15 and anti-PDL1 antibody in CT26 tumor model

[0198] A-Plan

[0199] Mice: A total of 60 5-week-old female BALB / C mice weighing 15-19 g were ordered from Envigo. The animals were acclimated for one week in the C3M animal facility. The animals were housed in IVC cages (5 per cage) and individual mice were identified by ear tags. All animals were allowed free access to a standard certified commercial diet and sterile water during the study. The holding room was maintained under standard conditions: 18-24°C, 55-70% humidity, and 12h light / dark cycle. Two animals died when blood was drawn 1 week before dosing began.

[0200] All protocols used in this study have been approved by the Welfare and Ethics Committee of C3M.

[0201] 58 mice were randomly assigned to the following treatment groups

[0202]

[0203] Cells: CT26 cell line was thawed 2 weeks before the arrival of mice. These were cultured in RPMI medium supplemented with 10% FBS, 1% penicillin / streptomycin and 2% sodium pyruvate. Cells were plated at 0.8×10 in 5xT175 flasks 48 hours before subcutaneous injection. 6 This concentration allowed the cells to reach 70-80% confluence on the day of injection. Briefly, the cells were washed with PBS, detached from the flask using 3 ml of trypsin, collected with RPMI medium and centrifuged at 300 g for 5 min. These were then resuspended in PBS, counted and 0.5 × 10 6 cells / mouse (total 32 million cells, 80 mice) and centrifuged again to resuspend in 100 μl / mouse of PBS for subcutaneous injection (total 8 ml, 80 mice).

[0204] preparation:

[0205] HA15: 15% Kolliphor H15, 10% PEG400, 5% ethanol, 70% ultrapure water.

[0206] 1- In a sterile biosafety cabinet, Kolliphor HS15, PEG400 and ethanol were mixed in an appropriate ratio (3 / 2 / 1, v / v / v) and then the compound was formulated (Kolliphor HS15 was melted at 30°C).

[0207] 2- Weigh the appropriate amount of HA15 compound into a wheaton vial on a microbalance. Dissolve the compound in 3 volumes of the final solvent along with the above solution using a magnetic bar.

[0208] 3- After complete dissolution, add ultrapure water (7 parts final solution volume) to the wheaton vial and mix thoroughly by vortexing.

[0209] Antibodies (anti-PDL1 and IgG2b) were diluted in PBS before IP injection.

[0210] B-Results

[0211] After 13 days of treatment, the data showed that daily oral administration of HA15 reduced tumor volume. This reduction in CT26 tumor growth was statistically significant compared to the vehicle group. Furthermore, this was confirmed by weighing the tumors after the mice were terminated on day 13.

[0212] Biweekly dosing of anti-PDL1 together with daily administration of HA15 significantly reduced CT26 tumors compared to vehicle+IgG2b control and monotherapy (HA15) groups.

[0213] These results suggest that HA15 can also enhance anti-PDL1 responses. It can therefore be concluded that HA15 allows for the enhancement of the effects of immune checkpoint inhibitors in general.

[0214] The intratumoral levels of GRP78 in treated mice were as shown in Figure 3 As shown in this figure, the combination therapy HA15+anti-PDL1 allowed to significantly reduce the intratumoral levels of GRP78 in patients compared with monotherapy containing HA15 or anti-PDL1 alone.

[0215] Example 3: Combination of HA15 with different anticancer treatments

[0216] method

[0217] Cell lines and reagents: Different cell lines were purchased from ATCC. Tumor cell lines were maintained at 37°C in a humidified atmosphere of 5% CO2 and in DMEM supplemented with 10% fetal bovine serum, high glucose, GlutaMAX TM Cells were grown in supplemented, pyruvate growth medium (ThermoFisher). Cells were treated with the indicated anticancer agents and HA15 at the indicated concentrations and times. All drugs were dissolved in DMSO.

[0218] Proliferation analysis: Cell proliferation was measured using WST-1 reagent from Abcam (#ab65473). On day 0, cells were placed in 96-well tissue culture plates. On day 1, cells were starved in serum (100 μL / well). On day 2, cells were treated with different drugs or DMSO at specified concentrations, repeated four times. 48 hours after treatment, WST-1 reagent (10 μL / well) was added. The plate was read at 450 nm at T0 on a Multiskan FC counter (ThermoFisher), and then read every hour until the OD reached 1.0. Cell proliferation is expressed as the percentage of absorbance after subtracting the background (T0).

[0219] Cells were treated with different concentrations of HA15 and different concentrations of the indicated anticancer agents for 48 h before WST-1 assay.

[0220] To evaluate the effect of HA15 in combination with another anticancer agent, we compared the observed and expected responses obtained from the combination treatment. The Bliss model was used to predict the combination effect of each drug.

[0221] The expected effect of the combination (Eexp) was estimated from each individual drug effect.

[0222] The results are provided in the table below. "SE" corresponds to significant efficacy of the combination of HA15 and the identified anticancer agent.

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236] These results suggest that HA15 is able to enhance responses to all several anticancer treatments, including chemotherapy and targeted therapy. It can therefore be concluded that HA15 can enhance the effects of anticancer treatments.

Claims

1. Combination of anticancer therapy with a compound of formula (I): in Q1 to Q5 are the same or different, indicating CR6 R1 represents a C6-C containing one or two fused rings 10 Aryl, wherein 2 to 5 carbon atoms may be replaced by heteroatoms selected from O, S, N and NR6, and finally 5 to 11 selected from R6, halogen, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2) p- NR6R7, (CH2) p- OR6 and (CH2) P Substituents of SR6 are substituted, R2 is SO2R1 or R6; R3 and R4 are the same or different and are selected from COR8 and R6 R5 represents R6, aryl, OR6, SR6, halogen, CN, NO2, CF3, OCF3, COOR6, SO2NR6R7, CONR6R7, NR6R7 and NHCOR6, R6 and R7 are the same or different and represent H or alkyl R8 is selected from H, alkyl, cycloalkyl, aryl, alkylaryl, wherein the aryl may be substituted by one to four identical or different R5 substituents, Or R8 represents -(CH2) q -NR6R7, p represents an integer from 0 to 6, q represents an integer from 0 to 6, wherein the thiazolyl group is attached to the 6-membered group at the meta or para position relative to the sulfonamide group, and wherein the thiazolyl group is attached to the 6-membered group at the alpha or beta position relative to the S atom, For use in treating cancer in patients who have been identified as overexpressing GRP78.

2. The combination for use according to claim 1, wherein the anti-cancer treatment is selected from chemotherapeutic agents, targeted therapies and immunotherapeutic agents such as immune checkpoint inhibitors.

3. The combination for use according to claim 1 or 2, wherein the anti-cancer therapy is an immune checkpoint inhibitor which is an anti-PD-1 or anti-PDL1 antibody.

4. The combination for use according to any one of claims 1 to 3, wherein the compound of formula (I) is selected from the group consisting of: N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)acetamide 5-(Dimethylamino)-N-(3-(2-(methylamino)thiazol-4-yl)phenyl)naphthalene-1-sulfonamide N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)-4-methylbenzamide N-(3-(2-aminothiazol-4-yl)phenyl)-5-(dimethylamino)naphthalene-1-sulfonamide N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)benzamide N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)trimethylacetamide 2-Fluoro-N-(3-(2-(methylamino)thiazol-4-yl)phenyl)benzenesulfonamide N-(4-(4-(Naphthalene-2-sulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(4-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(4-(2-Fluorophenylsulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(4-(2,4-difluorophenylsulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(4-(3-(trifluoromethyl)benzenesulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(3-(3-(trifluoromethyl)benzenesulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(4-(trifluoromethyl)benzenesulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(3-(4-methylphenylsulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(3-(2-Nitrophenylsulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(3-(3-Nitrophenylsulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(3-(phenylsulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(3-(Methylsulfonylamino)phenyl)thiazol-2-yl)acetamide N-(4-(4-(4-Methylphenylsulfonylamino)phenyl)thiazol-2-yl)acetamide as well as N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonylamino)phenyl)thiazol-2-yl)-6-aminohexanamide.

5. The combination for use according to any one of claims 1 to 4, wherein the compound has formula (III):

6. The combination for use according to any one of claims 1 to 5, wherein the cancer is selected from breast cancer, bladder cancer, cervical cancer, colorectal cancer, pancreatic cancer, head and neck cancer, Hodgkin's lymphoma, liver cancer, lung cancer, kidney cancer, skin cancer and stomach cancer.

7. The combination for use according to any one of claims 1 to 6, wherein the cancer is colorectal cancer.

8. The combination for use according to any one of claims 1 to 6, wherein the cancer is skin cancer, preferably melanoma.

9. The combination for use according to any one of claims 1 to 8, wherein the cancer is a non-immunogenic tumor.

10. The combination for use according to any one of claims 1 to 9, wherein the cancer is resistant to immunotherapy.

11. The combination for use according to claim 10, wherein the cancer is resistant to immune checkpoint inhibitors.

12. Test kit, comprising: - anticancer agents; and - Compound of formula (I) in Q1 to Q5 are the same or different, indicating CR6 R1 represents a C6-C containing one or two fused rings 10 Aryl, wherein 2 to 5 carbon atoms may be replaced by heteroatoms selected from O, S, N and NR6, and finally 5 to 11 selected from R6, halogen, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2) p- NR6R7, (CH2) p- OR6 and (CH2) P Substituents of SR6 are substituted, R2 is SO2R1 or R6; R3 and R4 are the same or different and are selected from COR8 and R6 R5 represents R6, aryl, OR6, SR6, halogen, CN, NO2, CF3, OCF3, COOR6, SO2NR6R7, CONR6R7, NR6R7 and NHCOR6, R6 and R7 are the same or different and represent H or alkyl R8 is selected from H, alkyl, cycloalkyl, aryl, alkylaryl, wherein the aryl may be substituted by one to four identical or different R5 substituents, Or R8 represents -(CH2) q -NR6R7, p represents an integer from 0 to 6, q represents an integer from 0 to 6, wherein the thiazolyl group is attached to the 6-membered group at the meta or para position relative to the sulfonamide group, and wherein the thiazolyl group is attached to the 6-membered group at the alpha or beta position relative to the S atom.

13. The kit of claim 12, for use in treating cancer in a patient who has been identified as overexpressing GRP78.

Images