Selective growth inhibition and induction of apoptosis in tumor cells

Abstract

The disclosed compounds include formula (M)m(G-T)n, a hydrate, a solvate, a pharmaceutically acceptable salt, or combination thereof, wherein M comprises a transition metal or a rare earth metal; m is 0 or 1; and n is 1, 2, or 3. Pharmaceutical compositions comprising such compounds, methods of using such compounds and compositions for selectively inhibiting growth and / or inducing apoptosis of a tumor cell; for inhibiting COPZ1 in a cell; and for inhibiting metastasis of a cancer cell, each by contacting the cell with a compound of formula (M)m(G-T)n. The compounds of formula (M)m(G-T)n and pharmaceutical compositions comprising such compounds may be used in any tumor cell where COPZ2 is down-regulated or the expression is altered relative to COPZ1. Down-regulation of COPZ2 has been observed in tumor cells including breast cancer, lung cancer, colorectal cancer, ovarian cancer, glioblastoma, thyroid cancer, cervical cancer, and pancreatic cancer.

Description

PCT Application (NO137-703WO) SELECTIVE GROWTH INHIBITION AND INDUCTION OF APOPTOSIS IN TUMOR CELLS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This PCT Application claims priority to U.S. Provisional Application 63 / 556,570,filed February 22, 2024, the content of which is herein incorporated by reference in its entirety. STATEMENT OF GOVERNMENT INTEREST

[0001] This disclosure was made with government support under grant number1P20GM109024 awarded by the National Institutes of Health. The government has certain rights in the disclosure. BACKGROUND

[0002] The Coatomer Protein Complex Subunit Zeta 1 (COPZ1) and Coatomer ProteinComplex Subunit Zeta 2 (COPZ2) are both integral components of the coatomer protein complex. This complex plays a pivotal role in mediating vesicular trafficking within cells, especially in the transport between the Golgi apparatus and the endoplasmic reticulum (ER).

[0003] Vesicular trafficking is initiated by the localized activation of a small GTPase at adonor membrane, triggered by the exchange of GDP for GTP, catalyzed by a guanine-nucleotide exchange factor. This activation prompts a conformational change in the GTPases, exposing hydrophobic sites that insert into the membrane. It also reveals binding sites for the recruitment of COPZ1 and COPZ2. The inhibition of COPZ1 and COPZ2 binding to GTPases leads to the collapse of the Golgi complex and ER, resulting in cell death. Notably, COPZ1 is expressed at almost the same level in both healthy and tumor cells, whereas COPZ2 is downregulated in tumor cells compared to normal ones. Consequently, normal cells can survive in the absence of COPZ1, by upregulation of COPZ2, whereas tumor cells are almost entirely reliant on COPZ1.

[0004] Therefore, COPZ1 inhibition may serve as a target for anti-cancer therapy.Accordingly, there remains a need in the art for COPZ1 inhibitors to promote selective tumor cell death by disrupting the Golgi complex and ER.PCT Application (NO137-703WO) BRIEF DESCRIPTION

[0005] Disclosed herein is A compound comprising formula (M)m(G-T)n, a hydrate, asolvate, a pharmaceutically acceptable salt, or combination thereof, wherein M comprises a transition metal or a rare earth metal; m is 0 or 1; n is 1, 2, or 3; wherein when m is 0, then n is 1, and when m is 1, then n is 2 or 3; G is represented by one of formulas G1 to G8 16bg"represents the attachment point between G-1 to G-8 to T; Z1-Z8 are each independently C, P(Rp), or S; X1-X8are each independently NR10, O, S, CH2, CH(Rx), or C(Rx)2; X9a, X9b, X10a, X10b, X11a, X11b, X12a, X12b, X13a, X13b, X14a, X14b, X15a, X15b, X16a, and X16b, are each independently NR10, O, CH2, CH(Rx), or C(Rx)2; Rxis a substituent; X1aand X2aare each independently NR10, O, or S; R10 is hydrogen or a substituent; r1a and r2a are each independently 0 or 1; R1aand R2aare each independently hydrogen, deuterium, or a C1-C6alkyl, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1- C6 alkyl is optionally replaced by at least one carbon-carbon double or triple bond; W1-W12are each independently hydrogen or a substituent;PCT Application (NO137-703WO) -V1-V2- and -V3-V4- are each independently a C1-C6 alkylene, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1-C6 alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene is optionally replaced by at least one O, S, or NR10; G’ and G” are each independently a 5- to 6-membered ring, a bridged bicyclic ring, system, or a fused ring system; Rg’and Rg”are each independently a substituent; g’ and g” are each independently 0 to 5; T is represented by one of Formula T1, T2, or T3 3)represents the attachment point between T1 to T3 and G; A is a 5- or 6-membered aryl ring, or a 5- or 6-membered heteroaryl ring; a and b are each independently 0 to 5, Raand Rbare each independently a substituent; Y1 and Y2 are each independently –CH2, -CH(R1), –C(R1)(R2), O, S, NR10, -Z(=X’)x’ provided that one of Y1 and Y2 is -Z(=X’)x’; R1and R2are each independently a substituent; Z is C, P(Rp’), or S, wherein Rp’is hydrogen or a substituent; X1 is NR10, O, S, CH2, CH(Rx), or C(Rx)2; x is 1 or 2; Y3is CH, C(Ry), or N; Lb is a single bond, a C1-C6 alkylene optionally substituted with at least one substituent, in which any carbon-carbon single bond of the C1-C6 alkylene is optionally replaced by at leastPCT Application (NO137-703WO) one carbon-carbon double or triple bond, and any methylene of the C1-C6 alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Se, Ge, or Si; B is a 5-membered ring, 6-membered ring, a fused ring system thereof, or a bicyclic ring; the substituents each independently comprise: hydroxyl, deuterated hydroxyl, thiol, deuterated thiol, cyano, halogen, isonitrile (-NC), or nitro; or a C1-C12alkyl, a C2-C12alkenyl, a C2-C12alkynyl, a C3-C6cycloalkyl, a C1-C6alkyl(C3- C6 cycloalkyl), a C1-C6 alkyl(C3-C6 cycloalkenyl), a C3-C6 cycloalkenyl, a C2- C6 heterocycloalkyl, a C2-C6 heterocycloalkenyl, a C1-C6 alkyl(C2-C6 heterocycloalkyl), a C1- C6alkyl(C2-C6heterocycloalkenyl), a C5-C12aryl, C2-C30heteroaryl, a C1-C6alkyl (C5-C12aryl), or a C1-C6 alkyl (C2-C30 heteroaryl), optionally substituted with a deuterium, a halogen, or a combination thereof, wherein any carbon-carbon single bond of the C1-C12alkyl and the C1-C6alkyl is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of the C1-C12 alkyl and the C1-C6 alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Se, Ge, or Si.

[0006] Disclosed herein is a pharmaceutical composition, comprising the above-referencedcompound of and a pharmaceutically acceptable excipient.

[0007] Disclosed herein is a method for selectively inhibiting growth and / or inducingapoptosis of a tumor cell, comprising contacting the cell with an effective amount of the above- referenced compound.

[0008] Disclosed herein is a method for inhibiting coatomer protein complex subunit zeta 1(COPZ1) in a cell, comprising contacting the cell with an effective amount of the above- referenced compound.

[0009] Disclosed herein is a method inhibiting metastasis of a cancer cell, comprisingcontacting the cell with an effective amount of the above-referenced compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The novel features of the disclosure are set forth with particularity in the appendedclaims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrativePCT Application (NO137-703WO) embodiments, in which the principles of the disclosure are used, and the accompanying drawings of which:

[0011] FIG. 1 includes exemplary compounds 1-4 of the presently-disclosed subject matter.

[0012] FIG. 2A and 2B provide renderings of (FIG. 2A) COPZ1 structure docked withcompounds 1-4 (blue), amino acid Lys 42 (pink); and (FIG.2B) COPZ2 structure docked with compounds 1-4, amino acid Met63 (blue).

[0013] FIGS. 3A-3D includes data from cell viability evaluation of compounds 1-4 againstPancreatic Ductal Adenocarcinoma (PDAC) cells.

[0014] FIG. 4 illustrates the position of compounds 3, 4, and GTP into the binding pocket ofCOPZ1 protein.

[0015] FIG. 5 illustrates the position of compounds 1 and 2 into the binding pocket ofCOPZ1 protein showing the inverse binding position.

[0016] FIG. 6 includes results of Quantitative Polymerase Chain Reaction (QPCR) analysisof COPZ1 and COPZ2 in PDAC cells and Human Pancreatic Nestin-Expressing (HPNE) cells, which are normal pancreatic cells.

[0017] FIG. 7 includes results of cell death assay analysis for HPNE and MIA PaCa-2(PDAC cell).

[0018] FIG. 8 includes PK-PD theoretical studies for compounds 1-4.

[0019] FIG. 9 shows the cell cycle arrest analysis using compounds 3 and 4. Doxorubicinwas used as a positive control.

[0020] FIG. 10 Lipid peroxidase assay to assess whether cells were dying by ferroptosisusing COPZ1 inhibitor candidates in HPNE and Mia PaCa-2 cells.

[0021] FIG. 11 shows siRNA Transfection – COPZ1 Knockdown in HPNE healthy cells.

[0022] FIGS. 12A-12D shows data from cell viability evaluation of compounds 1-4 againstHCC1143 (breast cancer) and A-375 (malignant melanoma) cells. DETAILED DESCRIPTION

[0023] The details of one or more embodiments of the presently-disclosed subject matter areset forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly thePCT Application (NO137-703WO) specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom. In case of conflict, the specification of this document, including definitions, will control.

[0024] Chemotherapy remains a mainstay of treatment of cancers, especially for advanced ormetastatic stages. These drugs can work in various ways, such as inhibiting cell division, damaging DNA, or interfering with other essential processes within the cell. While these treatments can help control the disease and extend life, they are not typically curative for many types of cancer, including pancreatic cancer. Almost all of the conventional cancer drugs act on molecular targets that are involved in cell proliferation. As such, known cancer drugs kill proliferating but not growth-arrested tumor cells, which include dormant tumor cells and tumor stem cells that will eventually cause the tumor to recur.

[0025] Tumor onset and progression involves activation of an oncogene, inactivation oftumor suppressor genes, deregulation of epigenetic landscape and altered interaction with microenvironment. Several tumor cell types depend upon the continued activity of certain oncogenes (i.e., “oncogene addiction”). Inhibitors of oncogenes such as HER2 (e.g., herceptin for breast cancer), BCR-ABL fusion gene for chronic myeloid leukemia, KIT for digestive tumors, EGFR and ALK for non-small-cell lung cancer, and BRAF for melanoma eradicate tumor cells containing enhanced oncogenic signaling while sparing the normal tissue, providing an excellent therapeutic opportunity. Remissions were accomplished using this approach, however, additional mutations and the involvement of alternative / compensatory / adaptive pathways drive drug resistance development. In addition, targeting oncogene addiction can only be applied to certain types of tumors because most mutations (i.e., oncogene activating mutations and loss-of-function mutations in tumor suppressor genes) found in tumors are not directly druggable.

[0026] Alternative strategies are needed to treat malignancies driven by undruggableoncogenes or loss of tumor suppressor genes and to overcome drug resistance phenomena also occurring in cancers addicted to actionable drivers. Alternatively, non-oncogene dependencies, also known as non-oncogene addiction (NOA), are genes that cancer cells rely on for survival. These genes are not usually mutated or abnormally expressed in normal cells. Stated another way, NOA refers to genes / pathways that are not oncogenic, but essential for the tumor cell growth / survival while dispensable for normal cells.PCT Application (NO137-703WO)

[0027] To that end, while most of the COPI components are expressed at comparable levelsin normal and tumor cells, COPZ2 is drastically downregulated in the majority of tumors. Hence, normal cells express two isoforms of the zeta subunit of COPI, Z1 and Z2, whereas tumor cells have only Z1, due to the silencing of the COPZ2 gene encoding COPZ2. This suggests that normal cells survive the loss of Z1 because Z2 substitutes for it in the COPI complex, whereas tumor cells have no such fallback. Therefore, targeting COPZ1 represents a promising therapeutic approach for the treatment of various cancers including pancreatic cancer, considering its specificity for cancer cells and the lack of effect on normal cells.

[0028] The presently-disclosed subject matter includes compounds of the formula (M)m(G-T)n, pharmaceutical compositions comprising such compounds, methods of using such compounds and compositions for selectively inhibiting growth and / or inducing apoptosis of a tumor cell; for inhibiting COPZ1)in a cell; and for inhibiting metastasis of a cancer cell, each by contacting the cell with a compound of formula (M)m(G-T)n. In some embodiments, the presently-disclosed subject matter includes structurally-unique compounds that inhibit COPZ1 in tumor cells. The compounds of formula (M)m(G-T)n and pharmaceutical compositions comprising such compounds may be used in any tumor cell where COPZ2 is down-regulated or the expression is altered relative to COPZ1. Down-regulation of COPZ2 has been observed in tumor cells including breast cancer, lung cancer, colorectal cancer, ovarian cancer, glioblastoma, thyroid cancer, cervical cancer, and pancreatic cancer.

[0029] The compounds of formula (M)m(G-T)n, where M is a metal, for example, atransition metal or a rare earth metal. M may be present (m is 1) or is may be absent (m is 0). When m is 1, then 2 or 3 of the moieties represented by G-T are present (i.e., M(G-T)2 or M(G- T)3), wherein each occurrence of the moiety represented by G-T may be the same or different. When m is 1, each occurrence of G-T includes a moiety capable of forming a complex with M. For example, “a moiety capable of forming a complex with M” may be represented by U or Y1’- U, wherein: U is hydroxyl (-OH), thiol (-SH), cyano (-CN), fluorine (-F), isonitrile (-NC), nitro (-NO2), -N=O(Y2’), NH2, -NH-Y2’, -N(Y2’)2, -O-Y2’, -S-Y2’, -S(=O)(Y2’), -S(=O)(Y2’)(NY2’), - S(=O)2(Y2’), aldehyde (–CH(=O)), -C(=O)Y2’, -C(=S)Y2’, -O-C(=O)Y2’,-O-C(=S)Y2’, -S- C(=O)Y2’, -S-C(=S)Y2’, -C(=O)-OY2’, -C(=S)Y2’, -C(=S)-OY2’, -C(=O)-SY2’, -C(=S)-SY2’, -O- C(=O)-OY2’, -O-C(=S)-OY2’, -O-C(=O)-SY2’, -O-C(=S)-SY2’, -S-C(=O)-OY2’, -S-C(=S)-OY2’, - S-C(=O)-SY2’, -S-C(=S)-SY2’,-C(=O)-NH2, -C(=O)-NH(Y2’), -C(=O)-N(Y2’)2, -C(=S)-NH2, -PCT Application (NO137-703WO) C(=S)-NH(Y2’), -C(=S)-N(Y2’)2, -NH-C(=O)-Y2’, -N(Y2’)-C(=O)-Y2’, -NH-C(=S)-Y2’, -N(Y2’)- C(=S)-Y2’, NH-S(=O)2-Y2’, N(Y2’)-(=O)2-Y2’, -O-C(=O)-NH2, -O-C(=O)-NH(Y2’), -O-C(=O)- N(Y2’)2, -O-C(=S)-NH2, -O-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, -NH-C(=O)-NH2, -NH-C(=O)- NH(Y2’), -NH-C(=O)-N(Y2’)2, -NH-C(=S)-NH2, -NH-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, - NH(Y2’)-C(=O)-NH2, -NH(Y2’)-C(=O)-NH(Y2’), -NH(Y2’)-C(=O)-N(Y2’)2, -NH(Y2’)-C(=S)- NH2, -NH(Y2’)-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, carboxylic acid (C(=O)OH), sulfonic acid (- SO3H), -C(=O)NH-NH2, -C(=S)NH-NH2, -S(=O)NH-NH2, -C(=O)NH-NH2, -C(=S)NH-NH2, or -C(=NH-NH2)Y2’; each occurrence of Y1’ and each occurrence of Y2’ independently comprise C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C3 alkyl(C3-C6 cycloalkyl), C1- C3alkyl(C3-C6cycloalkenyl), C3-C6cycloalkenyl, C2-C6heterocycloalkyl, C2- C6 heterocycloalkenyl, C1-C3 alkyl(C2-C6 heterocycloalkyl), C1-C3 alkyl(C2- C6 heterocycloalkenyl), C5-C12 aryl, C2-C30 heteroaryl, C1-C6 alkyl (C2-C6 heteroaryl), wherein U Y1’-U are each optionally substituted with halogen, deuterium, or a combination thereof.

[0030] In a preferred aspect, the moiety capable of forming a complex with M includes acarboxylic acid, a carboxylic ester, a sulfone, and a sulfonic acid.

[0031] When m is 0, then no metal is present and 1 moiety represented by G-T is present(i.e., G-T). In some aspects, m is 0, n is 1, and T is represented by T1 or T2. In some aspects, m is 1, n is 2 or 3, and T is represented by T1. In some aspects, m is 1, n is 2 or 3, and T is represented by T3.

[0032] In formula (M)m(G-T)n, G is represented by one of formulas G1-G8:g"Z1-Z8are each independently C, P(Rp), or S;PCT Application (NO137-703WO) X1-X8 are each independently NR10, O, S, CH2, CH(Rx), or C(Rx)2; X9a, X9b, X10a, X10b, X11a, X11b, X12a, X12b, X13a, X13b, X14a, X14b, X15a, X15b, X16a, and X16b, are each independently NR10, O, CH2, CH(Rx), or C(Rx)2; Rx is a substituent; X1a and X2a are each independently NR10, O, or S; R10is hydrogen or a substituent; r1a and r2a are each independently 0 or 1; Rp is hydrogen or a substituent; R1a and R2a are each independently hydrogen, deuterium, or a C1-C6 alkyl, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1- C6 alkyl is optionally replaced by at least one carbon-carbon double or triple bond; W1-W12 are each independently hydrogen or a substituent; the moieties represented by V1-V2and V3-V4are each independently a C1-C6alkylene, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1-C6 alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene is optionally replaced by at least one O, S, or NR10; G’ and G” are each independently a 5- to 6-membered ring, a bridged bicyclic ring system, or a fused ring system; Rg’ and Rg” are each independently a substituent; g’ and g” are each independently 0 to 5.

[0033] In formula (M)m(G-T)n, T is represented by one of formulas T1-T3:A is a 5- or 6-membered aryl ring, or a 5- or 6-membered heteroaryl ring;PCT Application (NO137-703WO) a and b are each independently 0 to 5, Ra and Rb are each independently a substituent; Y1and Y2are each independently –CH2, -CH(R1), –C(R1)(R2), O, S, NR10, -Z(=X’)x’provided that one of Y1 and Y2 is -Z(=X’)x’; R1 and R2 are each independently a substituent; Z is C, P(Rp’), or S; X’ is NR10, O, S, CH2, CH(Rx), or C(Rx)2; x’ is 1 or 2; Y3 is CH, C(Ry), or N; Lbis a single bond, a C1-C6alkylene optionally substituted with at least one substituent, in which any carbon-carbon single bond of the C1-C6 alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of the C1-C6 alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Se, Ge, or Si; and B is a 5-membered ring, 6-membered ring, a fused ring system thereof, or a bridged bicyclic ring system.

[0034] In formula (M)m(G-T)n, represents the attachment point between one of G1 to G8and one of T1 to T3. The structures of GT where T is represented by T1 and G is represented by G1-G8 are each shown below (i.e., G1-T1, G2-T1, G3-T1, G4-T1, G5-T1, G6-T1, G7-T1, and G8-T1).PCT Application (NO137-703WO)is represented by one ofG1-G8 are each shown below (i.e., G1-T2, G2-T2, G3-T2, G4-T2, G5-T2, G6-T2, G7-T2, and G8-T2).PCT Application (NO137-703WO)one of formulas G1-G8 are each shown below (i.e., G1-T3, G2-T3, G3-T3, G4-T3, G5-T3, G6- T3, G7-T3, and G8-T3). (R) (R (Rb b b)bb)bB BPCT Application (NO137-703WO)

[0037] In any of G1-G8, T1-T3, G1-T1, G2-T1, G3-T1, G4-T1, G5-T1, G6-T1, G7-T1, G8-T1, G1-T2, G2-T2, G3-T2, G4-T2, G5-T2, G6-T2, G7-T2, G8-T2, G1-T3, G2-T3, G3-T3, G4- T3, G5-T3, G6-T3, G7-T3, and G8-T3, any hydrogen may be replaced with a deuterium; and / or functional groups capable for forming salts may be either in free base form or salt form. When m is 1 and M (i.e. transition metal or rare earth metal) is present, functional groups capable of forming salts other than those functional groups that form salts with M may be either in free base form or salt form. The metal “M” in M(G-T)nis a transition metal or a rare earth metal. Exemplary transition metals include Cu, Ag, Zn, and Ni. Exemplary rare earth metals include La, Eu, Tb, and Dy.

[0038] In G1-G4, G1-T1, G2-T1, G3-T1, G4-T1, G1-T2, G2-T2, G3-T2, G4-T2, and G1-T3,G2-T3, G3-T3, and G4-T3, the designations X1-X8 are each independently NR10, O, S, CH2, CH(Rx), or C(Rx)2 and Z1-Z8 are each independently C, P(Rp), or S. In some aspects, the moieties represented by Z1=X1, Z2=X2, Z3=X3, Z4=X4, Z5=X5, Z6=X6, Z7=X7, and Z8=X8may each independently be: –C=NR10, –P(Rp)=NR10, –S=NR10, C=O, –P(Rp)=O, –S=O, C=S, –P(Rp)=S, – C=CH2, –P(Rp)=CH2, –S=CH2, C=CH(Rx), –P=CH(Rx), –S=CH(Rx), C=C(Rx)2 , –P=C(Rx)2, or – S=C(Rx)2, wherein: Rpis a hydrogen or a substituent; Rxis a substituent that is not hydrogen, and each occurrence of Rpand Rxmay be the same or different. In some aspects, the moieties represented by Z1=X1, Z2=X2, Z3=X3, Z4=X4, Z5=X5, Z6=X6, Z7=X7, and Z8=X8 may each independently be: –C=NR10, –C=O, –P=O, –S=O, –C=S, or –P=S. In a preferred aspect, at least one of the moieties represented by Z1=X1and Z2=X2; Z3=X3and Z4=X4; Z5=X5and Z6=X6; and Z7=X7 and Z8=X8 is –C=O or –C=S, more preferably –C=O. In a more preferred aspect, both of the moieties represented by the following pairs: Z1=X1 and Z2=X2; Z3=X3 and Z4=X4; Z5=X5 and Z6=X6; and Z7=X7and Z8=X8are either –C=O or –C=S, preferably –C=O.

[0039] In G5-G8, G5-T1, G6-T1, G7-T1, G8-T1, G5-T2, G6-T2, G7-T2, G8-T2, G5-T3, G6-T3, G7-T3, and G8-T3, the designations X9a, X9b, X10a, X10b, X11a, X11b, X12a, X12b, X13a, X13b, X14a, X14b, X15a, X15b, X16a, and X16bare each independently NR10, O, CH2, CH(Rx), or C(Rx)2, wherein Rxis a substituent that is not hydrogen, and each occurrence of Rxmay be the same or different. In some aspects, the moieties represented by Z9=X9a, Z9=X9b, Z10=X10a, Z10=X10b, Z11=X11a, Z11=X11b, Z12=X12a, Z12=X12b, Z13=X13a, Z13=X13b, –Z14=X14a, Z14=X14b, Z15=X15a, Z15=X15b, Z16=X16a, and Z16=X16bmay each independently be: S=NR10, S=O, S=CH2, S=CH(Rx), or S=C(Rx)2, wherein Rx is a substituent that is not hydrogen, and each occurrence of Rx may bePCT Application (NO137-703WO) the same or different. In some aspects, the moieties represented by the following “Z=X” pairs, i.e., S=X9a and S=X9b; S=X10a and S=X10b; S=X11a and S=X11b; S=X12a and S=X12b; S=X13a and S=X13b; S=X14aand S=X14b; S=X15aand S=X15b; and S=X16aand S=X16bmay each independently be: S=NR10 or S=O. In a preferred aspect, at least one of the moieties from each of the following pairs S=X9a and S=X9b; S=X10a and S=X10b; S=X11a and S=X11b; S=X12a and S=X12b; S=X13aand S=X13b; S=X14aand S=X14b; S=X15aand S=X15b; and S=X16aand S=X16bis S=O (e.g., functional group represented by S(=X9a)(=X9b) may be S(=O)(=NR10) or S(=O)2). In a more preferred aspect, both of the moieties from each of the following pairs S=X9a and S=X9b; S=X10a and S=X10b; S=X11a and S=X11b; S=X12a and S=X12b; S=X13a and S=X13b; S=X14a and S=X14b; S=X15aand S=X15b; and S=X16aand S=X16bare S=O (e.g., functional group represented by Z9(=X9a)(=X9b) is S(=O)2).

[0040] In formulas G1, G5, G1-T1, G1-T2, G1-T3, G5-T1, G5-T2, G5-T3, the moietiesrepresented by -V1-V2- and -V3-V4- are each independently a C1-C6alkylene, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1- C6 alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene is optionally replaced by at least one O, S, or NR10. The C1-C6alkylene may be a C2- C6alkylene or a C2-C4alkylene, wherein any carbon-carbon single bond of the C1-C6alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene is optionally replaced by at least one O, S, or NR10.

[0041] In some aspects, the moieties represented by -V1-V2- and -V3-V4- may be a C2-C6 alkylene or a C2-C4 alkylene and may not include any double or triple bonds. In some aspects, the moieties represented by -V1-V2- and -V3-V4- may be a C2-C6 alkylene or a C2-C4 alkylene and may not include any double or triple bonds, but at least one methylene may be replaced with O, S, or NR10. The moieties represented by -V1-V2- and -V3-V4- may be a C2-C6 alkylene and include 1, 2, or 3 double bonds and no methylenes are replaced with O, S, or NR10. In some aspects, the moieties represented by -V1-V2- and -V3-V4- may be a C2-C6alkylene and include 1, 2, or 3 double bonds and one or two methylenes are replaced with O, S, or NR10. The moieties represented by -V1-V2- and -V3-V4- may be a C2-C6 alkylene and may include 1, 2, or 3 triple bonds. The moieties represented by -V1-V2- and -V3-V4- may be a C2-C6 alkylene and may include 1, 2, or 3 triple bonds. In some aspects, the moieties represented by -V1-V2- and -V3-V4- include a combination of double bonds and triple bonds. The moieties represented by -V1-V2-PCT Application (NO137-703WO) and -V3-V4- may be a C2 or a C4 alkylene, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C2 or C4 alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene is optionally replaced by at least one O, S, or NR10. Exemplary C4 alkylene groups include: -(CH2)4-, -CH2-(CH2)2-CH2-, -CH2- (CH=CH)2-CH2-, -O-(CH2)2-O-, -O-(CH=CH)-O-, and the like. Although the foregoing exemplary C4alkylene groups recited are symmetrical, unsymmetrical groups such as - (CH=CH)2-(CH2)2are also contemplated.

[0042] In formulas G1 and G5, X1a and X2a are each independently NR10, O, or S; R1a and R2aare each independently hydrogen, deuterium, or a C1-C6 alkyl, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1-C6alkyl is optionally replaced by at least one carbon-carbon double or triple bond; and r1a and r2a are each independently 0 or 1. Exemplary moieties represented by X1a(R1a)r1a include hydroxyl, thiol, alkoxy, thioalkyl, and amine groups. When G is of formula G1, wherein X2is NR10, O, S, CH2, CH(Rx), or C(Rx)2and Z2 is C, N, or S, then the moiety represented by Z2(=X2)X1a(R1a)r1a may include carboxylic acids, esters, sulfonic acids, thioesters, amides, thioamides, and the like. When G is of formula G5, wherein X2is NR10, O, S, CH2, CH(Rx), or C(Rx)2and Z2is S, then the moiety represented by Z9(=X9a)X2a(R2a)r2aincludes sulfonamides, sulfonate esters, and sulfonic acids and salts thereof.

[0043] Referring to G4 and G8, ring G’ and ring G” are each independently a 5- to 6-membered ring, a bridged bicyclic ring system, or a fused ring system. As used herein, a 5- membered ring and a 6-membered ring encompass a non-aromatic carbocyclic ring, a non- aromatic heterocyclic ring, an aryl ring, and a heteroaryl ring. As used herein, “bridged bicyclic ring system” refers to a structure that includes two interconnected rings of atoms. Here, the two rings are connected by one or more atoms (the bridge), which are not included as ring formingatoms for either of the two rings. For example, norbornane and norbornene feature a bridgedbicyclic structure where the two rings are connected by a single carbon bridge. Other bridged bicyclic ring systems include two or more atoms in the bridge portion of the molecule. The ring members and bridge members may include carbon and / or heteroatoms. Exemplary bridged bicyclic ring systems include [2.2.1], [2.2.2], [3.3.1], [3.3.2], and the like. As used herein, “fused ring system” refers to two rings that share one atom or two or more adjacent atoms. For example, a fused system where the rings share two atoms includes naphthalene, in which the two benzene rings are fused together, sharing two carbon atoms. The fused ring system may include two orPCT Application (NO137-703WO) more rings, preferably two rings. A fused ring system also encompasses groups where one atom is shared by the two rings, referred to as a spiro ring system.

[0044] T1 may be represented by one of formulas (T1-1) to (T1-4)3)7) ring, or a 5-wherein all ring members are carbon and “heteroaryl ring” refers to an aromatic ring wherein at least one of the ring members is a heteroatom. In some aspects, “A” is a 6-membered aryl or a 6-membered heteroaryl ring. In some aspects, “A” includes a benzene ring, a pyridine ring, or a pyrimidine ring, each optionally substituted with Ra. In a preferred aspect, “A” is a benzene ring, optionally substituted with Ra.PCT Application (NO137-703WO)

[0047] In formulas T1 and T1-2 to T1-4, Y1 and Y2 are each independently –CH2, -CH(R1), –C(R1)(R2), O, S, NR10, -Z(=X’)x’, provided that one of Y1 and Y2 is -Z(=X’)x’, the remaining of Y1and Y2is –CH2, -CH(R1), –C(R1)(R2), O, S, or NR10; Z is C, P(Rp), or S; X’ is NR10, O, S, CH2, CH(Rx), or C(Rx)2; and x is 1 or 2. In some aspects, x may be 1; Z may be C, P(Rp), or S; and X’ may be NR10, O, S, CH2, CH(Rx), or C(Rx)2. In some aspects, x may be 2; Z may be S; and X’ may be NR10, O, S.

[0048] In formulas T1, T1-1 to T1-8, the “A” ring may be a 5-membered aryl ring; x’ may be1; Z may be C, P(Rp), or S; and X’ may be NR10, O, S, CH2, CH(Rx), or C(Rx)2; or x’ may be 2; Z may be S; and X’ may be NR10 or O. In some aspects, the “A” ring may be a 6-membered aryl ring; x’ may be 1; Z may be C, P(Rp), or S; and X’ may be NR10, O, S, CH2, CH(Rx), or C(Rx)2; or x’ may be 2; Z may be S; and X’ may be NR10, O, S. The “A” ring may be a 6-membered heteroaryl ring; x’ may be 1; Z may be C, P(Rp), or S; and X’ may be NR10, O, S, CH2, CH(Rx), or C(Rx)2; or x’ may be 2; Z may be S; and X’ may be NR10, O, S. In some aspects, the “A” ring may be a 6-membered heteroaryl ring; may be 1; Z may be C, P(Rp), or S; and X’ may be NR10, O, S, CH2, CH(Rx), or C(Rx)2; or x may be 2; Z may be S; and X’ may be NR10 or O. In some aspects, the “A” ring is a benzene ring, a pyridine ring, or a pyrimidine ring; x’ may be 1; Z may be C or S; and X’ may be NR10, O, or S. In some aspects, the “A” ring is a benzene ring, a pyridine ring, or a pyrimidine ring; x’ may be 2; Z may be S; and X’ may be NR10 or O. In a preferred aspect, the “A” ring is a benzene ring; x’ may be 1; Z may be C; and X’ may be NR10, O, or S

[0049] T may be represented by T2, which is guanosine triphosphate (“GTP”). T2 may be ina free base form or a pharmaceutically acceptable salt form.

[0050] T may be represented by formula T3. Lb is a single bond, a C1-C6 alkylene optionallysubstituted with at least one substituent, in which any carbon-carbon single bond of the C1- C6 alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of the C1-C6alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Se, Ge, or Si. In some aspects, Lbis a single bond, a C1- C6 alkylene optionally substituted with at least one substituent, in which any carbon-carbon single bond of the C1-C6 alkylene is optionally replaced by at least one carbon-carbon double or triple bond. In a preferred aspect, Lbis a single bond.PCT Application (NO137-703WO)

[0051] Ring “B” optionally substituted with Rb is a 5-membered ring, 6-membered ring, afused ring system thereof, or a bridged bicyclic ring system. Ring “B” optionally substituted with Rbmay be represented by one B-1 to B-4 or a fused ring system including two of B-1 to B-4. For example, a fused ring system may include two fused B-1 rings that share one or two ring- forming atoms; or a B-3 ring fused with a B-4 ring that share two ring-forming atoms; a B-2 ring fused with a B-4 ring, and the like.Referring to B-1 to B-4, variable B1 is C, CH, C(Rb), or N, and B2-B6 are each independently CH2, CH, CH(Rb), C(Rb),C(Rb)2, O, S, N, or NR10. Exemplary “B” rings include: cyclopentane, cyclopentadiene, tetrahydrofuran, tetrahydrothiophene, cyclohexane, cyclohexadiene, tetrahydropyran, tetrahydrothiopyran, thioxane, dithiane, morpholine, thiomorpholine, sulfolane, furan, thiophene, pyrrole, indene, benzofuran, benzothiophene, indole, oxazole, isoxazole, oxadiazole, isoxadiazole, oxatriazole, isoxatriazole, thiazole, isothiazole, thiadiazole, isothiadiazole, thiatriazole , isothiatriazole, pyrazole, imidazole, triazole, tetrazole, benzene, pyridine, pyrimidine, pyrazine, pyridazine, and triazine. In some aspects, ring “B” is benzene, a pyridine, pyrimidine, pyrazine, and pyridazine. In a preferred aspect, ring “B” is a benzene ring.

[0052] Substituents of formula (M)m(GT)n (i.e., “a substituent” and “at least one substituent”)include: hydroxyl, deuterated hydroxyl, thiol, deuterated thiol, cyano, halogen, isonitrile (-NC), amino, or nitro; or a C1-C12 alkyl, a C2-C12 alkenyl, a C2-C12 alkynyl, a C3-C6 cycloalkyl, a C1-C6 alkyl(C3- C6cycloalkyl), a C1-C6alkyl(C3-C6cycloalkenyl), a C3-C6cycloalkenyl, a C2- C6heterocycloalkyl, a C2-C6heterocycloalkenyl, a C1-C6alkyl(C2-C6heterocycloalkyl), a C1- C6 alkyl(C2-C6 heterocycloalkenyl), a C5-C12 aryl, C2-C30 heteroaryl, a C1-C6 alkyl (C5-C12 aryl), or a C1-C6 alkyl (C2-C30 heteroaryl), optionally substituted with a deuterium, a halogen, or a combination thereof, wherein any carbon-carbon single bond of the C1-C12 alkyl and the C1-C6 alkyl is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of thePCT Application (NO137-703WO) C1-C12 alkyl and the C1-C6 alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Se, Ge, or Si.

[0053] In some aspects, the substituent comprises selenium. For example, substituentsinclude a C1-C12 alkyl, a C2-C12 alkenyl, a C2-C12 alkynyl, a C3-C6 cycloalkyl, a C1-C6 alkyl(C3- C6 cycloalkyl), a C1-C6 alkyl(C3-C6 cycloalkenyl), a C3-C6 cycloalkenyl, a C2- C6heterocycloalkyl, a C2-C6heterocycloalkenyl, a C1-C6alkyl(C2-C6heterocycloalkyl), a C1- C6alkyl(C2-C6heterocycloalkenyl), a C5-C12aryl, C2-C30heteroaryl, a C1-C6alkyl (C5-C12aryl), or a C1-C6 alkyl (C2-C30 heteroaryl), wherein any methylene of the C1-C12 alkyl and the C1- C6 alkyl is replaced by Se. The foregoing groups may be optionally substituted with a deuterium, a halogen, or a combination thereof, and any carbon-carbon single bond of the C1-C12alkyl and the C1-C6 alkyl is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of the C1-C12 alkyl and the C1-C6 alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Ge, or Si.

[0054] In some aspects, substituents include ethers and thiothers. For example, substituentsinclude a C1-C12 alkyl, a C2-C12 alkenyl, a C2-C12 alkynyl, a C3-C6 cycloalkyl, a C1-C6 alkyl(C3- C6cycloalkyl), a C1-C6alkyl(C3-C6cycloalkenyl), a C3-C6cycloalkenyl, a C2- C6heterocycloalkyl, a C2-C6heterocycloalkenyl, a C1-C6alkyl(C2-C6heterocycloalkyl), a C1- C6 alkyl(C2-C6 heterocycloalkenyl), a C5-C12 aryl, C2-C30 heteroaryl, a C1-C6 alkyl (C5-C12 aryl), or a C1-C6 alkyl (C2-C30 heteroaryl), wherein any methylene of the C1-C12 alkyl and the C1- C6alkyl is replaced by O or S. The foregoing groups may be optionally substituted with a deuterium, a halogen, or a combination thereof, and any carbon-carbon single bond of the C1- C12 alkyl and the C1-C6 alkyl is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of the C1-C12alkyl and the C1-C6alkyl is optionally replaced by at least one NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Ge, Se, or Si. In a preferred aspect, substituents include –S-phenyl, optionally substituted with deuterium, halogen, alkoxy, or a combination thereof.

[0055] In some aspects, substituents of formula (M)m(GT)n include a fluorescein derivative.For example, fluorescein may be linked via a carboxyl group to G or T by a linker. In a preferred aspect, the linker includes a heteroatom at each end (e.g., S-alkyl-NR10-, -S-alkyl-O-, -S-alkyl- S).

[0056] In some aspects, substituents of formula (M)m(GT)n include:PCT Application (NO137-703WO) hydroxyl, deuterated hydroxyl, thiol, deuterated thiol, cyano, halogen, isonitrile (-NC), amino, or nitro; or a carboxylic acid or a salt thereof, a sulfonic acid or a salt thereof, or a phosphoric acid group or a salt thereof; a C1-C6 alkyl, a C1-C6 alkoxyl, or C1-C6 alkylthio, each optionally substituted by a deuterium, a halogen, cyano, isonitrile (-NC), amino, nitro, or a combination thereof; or Si(Q1)(Q2)(Q3), wherein Q1to Q3may be each independently a hydrogen, a C1-C6alkyl, a C1-C6 alkoxyl, or phenyl; Se(Q4), wherein Q4 is phenyl, optionally substituted with a deuterium, halogen, or a combination thereof.

[0057] In some aspects, substituents may be represented by U or Y1’-U, wherein: U ishydroxyl (-OH), thiol (-SH), cyano (-CN), fluorine (-F), isonitrile (-NC), nitro (-NO2), - N=O(Y2’), NH2, -NH-Y2’, -N(Y2’)2, -O-Y2’, -S-Y2’, -S(=O)(Y2’), -S(=O)(Y2’)(NY2’), - S(=O)2(Y2’), aldehyde (–CH(=O)), -C(=O)Y2’, -C(=S)Y2’, -O-C(=O)Y2’,-O-C(=S)Y2’, -S- C(=O)Y2’, -S-C(=S)Y2’, -C(=O)-OY2’, -C(=S)Y2’, -C(=S)-OY2’, -C(=O)-SY2’, -C(=S)-SY2’, -O- C(=O)-OY2’, -O-C(=S)-OY2’, -O-C(=O)-SY2’, -O-C(=S)-SY2’, -S-C(=O)-OY2’, -S-C(=S)-OY2’, - S-C(=O)-SY2’, -S-C(=S)-SY2’,-C(=O)-NH2, -C(=O)-NH(Y2’), -C(=O)-N(Y2’)2, -C(=S)-NH2, - C(=S)-NH(Y2’), -C(=S)-N(Y2’)2, -NH-C(=O)-Y2’, -N(Y2’)-C(=O)-Y2’, -NH-C(=S)-Y2’, -N(Y2’)- C(=S)-Y2’, NH-S(=O)2-Y2’, N(Y2’)-(=O)2-Y2’, -O-C(=O)-NH2, -O-C(=O)-NH(Y2’), -O-C(=O)- N(Y2’)2, -O-C(=S)-NH2, -O-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, -NH-C(=O)-NH2, -NH-C(=O)- NH(Y2’), -NH-C(=O)-N(Y2’)2, -NH-C(=S)-NH2, -NH-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, - NH(Y2’)-C(=O)-NH2, -NH(Y2’)-C(=O)-NH(Y2’), -NH(Y2’)-C(=O)-N(Y2’)2, -NH(Y2’)-C(=S)- NH2, -NH(Y2’)-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, carboxylic acid (C(=O)OH), sulfonic acid (- SO3H), -C(=O)NH-NH2, -C(=S)NH-NH2, -S(=O)NH-NH2, -C(=O)NH-NH2, -C(=S)NH-NH2, or -C(=NH-NH2)Y2’; each occurrence of Y1 and each occurrence of Y2’ independently comprise C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C1-C3alkyl(C3-C6cycloalkyl), C1- C3alkyl(C3-C6cycloalkenyl), C3-C6cycloalkenyl, C2-C6heterocycloalkyl, C2- C6 heterocycloalkenyl, C1-C3 alkyl(C2-C6 heterocycloalkyl), C1-C3 alkyl(C2- C6 heterocycloalkenyl), C5-C12 aryl, C2-C30 heteroaryl, C1-C6 alkyl (C2-C6 heteroaryl), wherein U Y1’-U are each optionally substituted with halogen, deuterium, or a combination thereof.PCT Application (NO137-703WO)

[0058] The alkyl, alkenyl, and alkynyl groups of the any of the foregoing substituentsinclude encompass linear and branched alkyl groups. For example, an alkyl group may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, a sec-pentyl, tert-pentyl, n-hexyl, iso-hexyl, sec-hexyl, tert-hexyl, n-heptyl, iso-heptyl, sec-heptyl, tert-heptyl, n-octyl, iso-octyl, sec-octyl, tert-octyl, n-nonyl, iso-nonyl, sec-nonyl, tert-nonyl, n- decyl, isodecyl, sec-decyl, and tert-decyl.

[0059] The compound of formula (M)m(GT)n may be one of the following compounds ofGroup I (see FIG.1). be one of the following compounds ofGroup II.PCT Application (NO137-703WO)O O O O Se O Se Se O ofPCT Application (NO137-703WO)wherein R is hydrogen or a substituent. Exemplary substituents include F, Cl, Br, CH3, and OMe.

[0063] Disclosed herein is a pharmaceutical composition, comprising the above-referencedcompound and a pharmaceutically acceptable excipient. The pharmaceutical composition may further include another cancer therapeutic (e.g., hormone therapy, immunotherapy, targeted therapy, chemotherapy).

[0064] The presently-disclosed subject matter includes a method for selectively inhibitinggrowth and / or inducing apoptosis of a tumor cell by contacting the cell with a compound as disclosed here.

[0065] The presently-disclosed subject matter further includes a method for inhibitingcoatomer protein complex subunit zeta 1 (COPZ1) in a cell by contacting the cell with a compound as disclosed here.

[0066] The presently-disclosed subject matter further includes a method for inhibitingmetastasis of a cancer cell by contacting the cell with a compound as disclosed here.

[0067] In some embodiments of the methods as disclosed herein, the cell with which thecompound is contacted is wherein the cell is a pancreatic cancer cell, a breast cancer cell, a melanoma cell, a lung cancer cell, a thyroid cancer cell, a glioblastoma cell, a cervical cancer cell, or a prostate cancer cell.

[0068] In some embodiments of the methods as disclosed herein, the cell is a coatomerprotein complex subunit zeta 2 (COPZ2)-deficient cell.

[0069] Some embodiments of the methods as disclosed herein further involve a step ofdetermining the activity of COPZ1 or COPZ2 for example, an MTT assay, a cell death assay, a binding assay, a cell cycle assay, and a COPZ1 knockdown of healthy cells.

[0070] In some embodiments of the methods as disclosed herein, the cell with which thecompound is contacted is in an animal subject. In some embodiments, the step of contacting the cell with the compound comprises administering the compound to the subject.PCT Application (NO137-703WO)

[0071] While the terms used herein are believed to be well understood by those of ordinaryskill in the art, certain definitions are set forth to facilitate explanation of the presently-disclosed subject matter.

[0072] While the terms used herein are believed to be well understood by those of ordinaryskill in the art, certain definitions are set forth to facilitate explanation of the presently-disclosed subject matter.

[0073] Unless defined otherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to which the disclosure(s) belong.

[0074] All patents, patent applications, published applications and publications, databases,websites and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety.

[0075] As used herein, the abbreviations for any protective groups, amino acids and othercompounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. (1972) 11(9):1726-1732).

[0076] The present application can “comprise” (open ended) or “consist essentially of” thecomponents of the presently disclosed subject matter as well as other ingredients or elements described herein. As used herein, “comprising” is open ended and means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended unless the context suggests otherwise.

[0077] The terms "a" and "an" do not denote a limitation of quantity, but rather denote thepresence of at least one of the referenced item.

[0078] Unless otherwise indicated, all numbers expressing quantities of ingredients,properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently-disclosed subject matter.

[0079] As used herein, the term “about,” when referring to a value or to an amount of mass,weight, time, volume, concentration or percentage is meant to encompass variations of in somePCT Application (NO137-703WO) embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, in some embodiments ±0.1%, in some embodiments ±0.01%, and in some embodiments ±0.001% from the specified amount, as such variations are appropriate to perform the disclosed method.

[0080] Recitation of ranges of values are merely intended to serve as a shorthand method ofreferring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or language indicating an example (e.g. , "such as"), is intended merely for illustration and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0001] The term “alkyl” refers to a linear or branched saturated aliphatic hydrocarbon group.“Alkenyl” refers to an alkyl group wherein a carbon-carbon single bond is replaced with a carbon-carbon double bond. “Alkynyl” refers to an alkyl group wherein a carbon-carbon single bond is replaced with a carbon-carbon triple bond. The term “cycloalkyl” refers to a saturated hydrocarbon monocyclic group. “Cycloalkenyl” refers to a cycloalkyl group wherein a carbon- carbon single bond (in the ring) is replaced with a carbon-carbon double bond. “Heterocycloalkyl” refers to a cycloalkyl group having carbon atoms and at least one heteroatom as ring forming atoms. “Heterocycloalkenyl” refers to a heterocycloalkyl group wherein a carbon-carbon single bond in the ring is replaced with a carbon-carbon double bond. “Aryl” refers to a carbocyclic aromatic ring. “Heteroaryl” refers to an aromatic ring including carbon atoms and at least one heteroatom as ring forming atoms. The term “alkyl(X)” refers to an alkylene group substituted with an “X” group. For example, “C1-C6alkyl(C3-C6cycloalkyl)” refers to a C1-C6alkylene (divalent) group substituted with a C3-C6cycloalkyl group.

[0002] "Pharmaceutically acceptable salts" includes derivatives of a compound of formula(M)m(GT)n, wherein the is modified by making acid or base addition salts thereof, and further refers to pharmaceutically acceptable solvates, including hydrates, and co-crystals of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are notPCT Application (NO137-703WO) limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, and combinations comprising one or more of the foregoing salts. The pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the active agent, a compound of formula (M)m(GT)n. For example, non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts. Pharmaceutically acceptable organic salts includes salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, Ν,Ν'- dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, asparginate, glutamate, and the like; and combinations comprising one or more of the foregoing salts; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, Ν,Ν' dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, asparginate, glutamate, and the like; and combinations comprising one or more of the foregoing salts.

[0003] As used herein, the term “pharmaceutically acceptable excipient” refers to a substanceuseful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22ndEd. Pharmaceutical Press, 2013, pp. 1049-1070).

[0004] As used herein, the term “treat”, “treating” or “treatment” of any disease or disorderrefers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting thePCT Application (NO137-703WO) development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0005] As used herein, the term “prevent”, “preventing” or “prevention” of any disease ordisorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder, e.g., prevent relapse after remission.

[0006] As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reductionor suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0007] As used herein, the term “a therapeutically effective amount” of a compound of thepresent disclosure refers to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.

[0008] As used herein, the term “subject” refers to mammals, primates (e.g., humans, male orfemale), dogs, rabbits, guinea pigs, pigs, rats and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0009] A “patient” is a human or non-human animal in need of medical treatment. Medicaltreatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In some embodiments the patient is a human patient.

[0010] As used herein, the term “anti-cancer agent” refers to a therapeutic agent that is usefulfor treating or controlling the growth of cancerous cells.

[0011] The presently-disclosed subject matter is further illustrated by the following specificbut non-limiting examples. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the presently disclosed subject matter. EXAMPLES

[0012] Synthesis of compound 1.

[0013] To a rapidly stirred solution of maleic anhydride in acetone at room temperature wasslowly added a solution of 4-aminoantipyrine in acetone. The resulting reaction mixture wasPCT Application (NO137-703WO) vigorously stirred at room temperature until the completion of the reaction as judged by TLC. The reaction mixture was filtered under vacuum, and the solid was washed with hexane (3×10 mL). The solid was dried over vacuum and recrystallized from ethanol / H2O (1:1) to afford the maleamic acid 1.

[0014] Synthesis of compound 2.

[0015] To a rapidly stirred solution of sodium acetate and acetic anhydride was slowly addedthe maleamic acid 1 at room temperature. The resulting reaction mixture was vigorously stirred at 80 °C until the completion of the reaction as judged by TLC. The organic compound was extracted with CHCl3, treated with saturated NaHCO3 solution, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting solid was purified by recrystallization from hexane to afford the desired maleimide 2.

[0016] Synthesis of compound 3.

[0017] The desired aryl thiol was add dropwise into a solution of maleimide 2 in methanol.The resulting reaction mixture was vigorously stirred for 30 minutes at room temperature. The organic phase was extracted with CH2Cl2, treated with saturated NaHCO3 solution, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting solid was purified by recrystallization from ethanol to afford the desired compound 3.

[0018] Synthesis of 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (4).

[0019] To a rapidly stirred solution of maleimide 2 (1.00 g, 3.59 mmol) in CH2Cl2 (10 mL)was slowly added the cyclopentadiene (6.11 mL, 7.27 mmol) at room temperature. The resulting reaction mixture was vigorously stirred at room temperature until the completion of the reaction as judged by TLC. The reaction mixture was cooled down to room temperature. The solid was filtered, dried under vacuum, and purified by recrystallization from hexane to afford the desired polycyclic compound 4. (1.00 g, 80% yield) as a white solid.

[0020] To obtain the compound of Group II, wherein M is a rare earth metal, maleicanhydride was reacted with the required aniline in ether at room temperature for approximately 3 hours. The precipitate was filtered, washed with cold water and dried at room temperature. Then, sodium hydroxide (NaOH) in ethanol was added to the reaction mixture at room temperature and stirred for 1 hour and thereafter the salt of the rare earth metal was added and the reactionPCT Application (NO137-703WO) mixture was stirred for more 2 hours. The obtained precipitate was filtered and dried at room temperature.

[0021] To obtain the compound of Group II, wherein M is a transition metal, maleicanhydride was reacted with the required aniline in ether at room temperature for approximately 3 hours. The precipitate was filtered, washed with cold water and dried at room temperature. Then, sodium hydroxide (NaOH) in ethanol was added to the reaction mixture at room temperature and stirred for 1 hour and thereafter the salt of the transition metal was added and the reaction mixture was stirred for more 2 hours. The obtained precipitate was filtered and dried at room temperature. Scheme 1.

[0022] For the compounds of Group III, the respective maleimide, diselenide, aniline, and10% of the Cu catalyst were dissolved in NMP. The reaction mixture was stirred for 2 hours at 140oC. Then, the organic phase was extracted with ethyl acetate and washed with brine. Then the solution was concentrated under reduced pressure and the product was purified by chromatographic column using a 0-15% hexane / ethyl acetate as eluent. Scheme 2.PCT Application (NO137-703WO)

[0023] For the compounds of Group IV, the GMP intermediate was first prepared as shownin Scheme 2, by refluxing maleic anhydride with GMP in diethyl ether. The GMP intermediate was converted to the final product as shown in Scheme 3. Specifically, the resulting reaction mixture was passed through DOWEX resin and then reacted with triethylammonium pyrophosphate, ZnCl2, and then treated with HCl. Scheme 3. GTP R OHAdenocarcinoma (PDAC) cells. The exemplary compounds were shown to be useful for inhibiting COPZ1 in COPZ2-deficient PDAC cells, thereby selectively killing the PDAC cells.

[0025] Related studies will involve selectively targeting COPZ1 in PDAC cells andidentification of Golgi disruption that leads tumor cells to apoptosis; exploring the ability of COPZ1 inhibitors to induce PDAC to apoptosis by collapsing Golgi complex and endoplasmic reticulum; optimizing PDAC killing with a new generation of COPZ1 inhibitors; and determine therapeutic efficacy and safety of small molecule-based COPZ1 inhibitor candidates in pancreatic cancer mouse models.

[0026] The presently-disclosed subject matter includes methods that involve killing tumorcells over healthy cells by disrupting the Golgi apparatus by selective inhibition of COPZ1 using a 1,4-dioxobutenyl structural small molecule scaffold. It is contemplated that COPZ1 could be the “Achilles Heel” of the tumor cells, and designing and synthesizing guanosine-1,4- dioxobutenyl compounds to inhibit COPZ1 could drive COPZ2-deficient tumor cells to apoptosis selectively. COPZ1-targeting therapy will selectively kill PDAC in any cell cycle stage, decreasing the possibility of tumor remission after initial treatment.PCT Application (NO137-703WO)

[0027] With reference to FIG. 1, a virtual analysis was conducted of compounds 1-4 with thebinding pockets of COPZ1 and COPZ2. Despite the structural similarity of COPZ1 and COPZ2, the slight difference in the amino acid sequence is sufficient to change the conformation of both proteins.

[0028] Compounds 1-4 are favored and strongly attracted to COPZ1 due to the proximity ofthe compounds and the alpha helix containing Lys42 (a polar amino acid) while a larger distance between the same alpha helix and the compounds positioned in the same binding pocket (FIG. 2A). For COPZ2, the interaction between the compound and the alpha helix occurs between the compounds and Met 63, a nonpolar amino acid that, when compared to COPZ1, reduces the overall attraction between the compounds and COPZ2 (FIG.2B).

[0029] To compare the cell viability results of PDAC cells (FIGS. 3A-3D) with the selectivebinding of COPZ1 instead of COPZ2, docking studies were performed to identify the differences that could influence the cell inhibition of compounds 1-4.

[0030] The best inhibitory performance of compounds 3 and 4 can be explained by theinteraction of these molecules with the binding pocket due to the position of the 1,4- dioxobutenyl moiety that lays in the same position as the GTP moiety from the activated ARF1- GTP COPZ1-recruiter (FIG.4). While compounds 1 and 2 are positioned inversely, favoring the recruitment and consequently favoring vesiculation (FIG.5).

[0031] The expression of COPZ1 and COPZ2 was also analyzed in PDAC cells and HPNE(normal pancreatic cell). As expected, it is possible to observe that both COPZ1 and COPZ2 are at almost the same level in the normal pancreatic cell, while expression of COPZ2 in PDAC is downregulated (FIG.6).

[0032] Preliminary binding affinity (MST analysis) showed that compounds 2-4 bind intoCOPZ1, corroborating the virtual studies (Table 1). Table 1. MST analysis for COPZ1 and compounds 1-4. Target Ligand Binding Biological Detected? Kd (nM) [Confidence] Triplicate? CopZ1 (35 nM) No N / A NoCopZ1 (35 nM) Yes 17.6 [1.56] NoPCT Application (NO137-703WO) 600.0 CopZ1 (35 nM) 3 Yes Ligand Induced Fluorescence (SDS No Test) CopZ1 (35 nM) 4 (5 mM) Yes 524.0 No

[0033] The cell death assay was also performed, and results indicate that compounds 1-4selectively kill PDAC cells while the normal cells are barely affected. BFD means brefeldin. (FIG.7).

[0034] Additionally, theoretical pharmacokinetics and pharmacodynamics analysis wereperformed, and the results are shown in FIG.8.

[0035] The Golgi disruption assay was performed to learn whether tumor cells were dying byGolgi disruption. Compounds were able to disrupt Golgi apparatus at the concentration of 40µM which is higher than the concentration used for inhibition and cell death assays (FIG.9). The result indicated that another mechanism is involved in the cell death.

[0036] To learn if Golgi disruption was the main reason for the cell death, cell cycle arrestanalysis was performed using compounds 3 and 4. Doxorubicin and cisplatin were used as positive control and arrested the cells in the G2 / M which is related to genomic DNA damage that leads to apoptosis. Compounds 3-4 did not cause DNA damage and arrested the cells in the G1 phase which is correlated to cell growth before DNA replication (see FIG.9).

[0037] The cell cycle experiments, were performed by flow cytometry in independenttriplicates.2 x 105of HPNE cells with COPZ1 knockdown were seeded in 6 well plates and incubated with 5% CO2 at 37°C for 24 hours. After that, the treatments with 50 μg / mL of cisplatin and doxorubicin (positive control), 1% DMSO (negative control) and with the IC50 of compounds 3 and 4 were performed. After 24 hours the cells were collected by enzymatic cleavage, centrifuged at 1200 rpm for 5 minutes and the supernatant was discarded. The pellet was resuspended in 100μL of PBS and transferred to a cryotube. The acquisition of 10.000 events was performed on a BD Accuri® C6 cytometer and then analyzed by BD Accuri® C6 Software.

[0038] To verify the influence of the treatments on the cell cycle, 5μL of RNAse (2mg / mL)were added to the cryotube containing 100μL of cell suspension (in PBS) and incubated at 37oC,PCT Application (NO137-703WO) 5% CO2, for 30 minutes. Then, 100 μL of the lysis solution (20 mg Sodium Citrate Dihydrate, 20 μL Triton X 100 and 20 mL PBS) and 5 μL of Propidium Iodide (50 μg / mL) were added. The cryotube was incubated on ice for 30 minutes protected from light prior to acquisition.

[0039] To validate the mechanism of death, a ferroptosis assay was performed. For thisexperiment, lipid peroxidation was assessed, the Click-iT™ Lipid Peroxidation Imaging Kit was used to detect lipid peroxidation in HPNE (Human Pancreatic Normal Epithelial) and MIA PaCa 2 cells, employing cumene hydroperoxide as a positive control to induce lipid peroxidation. The kit includes all necessary components for the click reaction, such as L-ascorbic acid (LAA) and Alexa Fluor™ 488 azide, which allow for the fluorescent labeling of oxidized lipids. The experimental setup also included negative and positive control groups to validate the assay. In the HPNE cells, no significant lipid peroxidation was observed, indicating that the normal pancreatic epithelial cells were resistant to lipid oxidative damage under the conditions tested. In contrast, the MIA PaCa 2 cells, a pancreatic cancer cell line, exhibited a noticeable increase in lipid peroxidation when treated with the test compounds, suggesting that the compounds induced oxidative stress in these cancer cells (FIGS.10A-10B).

[0040] The knockdown assay of HPNE (healthy pancreatic cell) was performed. The HPNEincludes both COPZ1 and COPZ2 at the same level of expression. COPZ1 / COPZ2 knockdown was accomplished using siRNA gene silencing, that acts in the RNA interference pathway, by interfering with the expression of genes with complementary nucleotide sequence to that siRNA, inducing mRNA degradation. The COPZ1 knockdown exhibited greater than 95% COPZ1 reduced expression in HPNE cells transfected with COPZ1 siRNAs, but not with GAPDH or scramble siRNAs. Also noteworthy was that COPZ2 expression remained stable in cells transfected with GAPDH or COPZ1 siRNAs. These results demonstrate that we knocked down COPZ1 mRNA levels in a highly specific manner, leaving COPZ2 expression unaffected (FIG. 11).

[0041] Compounds 1-4 against HCC1143 (breast cancer) and A-375 (malignantmelanoma) cells and results were similar to pancreatic tumor cells (FIGS.12A-12D).

[0042] To summarize, in the selective inhibition of COPZ1 in COPZ2-deficient PDAC cells,four compounds were selected as candidates for killing selectively PDAC cells. Inhibition assay (MTT) studies were performed with 10 compounds, including Brefeldin as a positive control for Golgi disruption and the chemical fragments used to synthesize the COPZ1 inhibitors. Cell deathPCT Application (NO137-703WO) assays were also performed, and corroborate with the inhibition assays. Virtual pharmacokinetics and pharmacodynamics were also performed, and obtained properties of the compounds will be used as a preliminary result for animal studies. After testing the orthotopic

[0043] It will be understood that various details of the presently disclosed subject matter canbe changed without departing from the scope of the subject matter disclosed herein. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.

Claims

PCT Application (NO137-703WO) CLAIMS What is claimed is:

1. A compound comprising formula (M)m(G-T)n, a hydrate, a solvate, a pharmaceutically acceptable salt, or combination thereof, wherein M comprises a transition metal or a rare earth metal; m is 0 or 1; n is 1, 2, or 3; wherein when m is 0, then n is 1, and when m is 1, then n is 2 or 3; G is represented by one of formulas G1 to G8 16bg"represents the attachment point between G-1 to G-8 to T; Z1-Z8are each independently C, P(Rp), or S; X1-X8 are each independently NR10, O, S, CH2, CH(Rx), or C(Rx)2; X9a, X9b, X10a, X10b, X11a, X11b, X12a, X12b, X13a, X13b, X14a, X14b, X15a, X15b, X16a, and X16b, are each independently NR10, O, CH2, CH(Rx), or C(Rx)2; Rx is a substituent; X1a and X2a are each independently NR10, O, or S; R10is hydrogen or a substituent; r1a and r2a are each independently 0 or 1; R1a and R2a are each independently hydrogen, deuterium, or a C1-C6 alkyl, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1- C6alkyl is optionally replaced by at least one carbon-carbon double or triple bond;PCT Application (NO137-703WO) W1-W12 are each independently hydrogen or a substituent; -V1-V2- and -V3-V4- are each independently a C1-C6 alkylene, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1-C6alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene is optionally replaced by at least one O, S, or NR10; G’ and G” are each independently a 5- to 6-membered ring, a bridged bicyclic ring, system, or a fused ring system; Rg’ and Rg” are each independently a substituent; g’ and g” are each independently 0 to 5; T is represented by one of Formula T1, T2, or T3 3)represents the attachment point between T1 to T3 and G; A is a 5- or 6-membered aryl ring, or a 5- or 6-membered heteroaryl ring; a and b are each independently 0 to 5, Ra and Rb are each independently a substituent; Y1 and Y2 are each independently –CH2, -CH(R1), –C(R1)(R2), O, S, NR10, -Z(=X’)x’ provided that one of Y1and Y2is -Z(=X’)x’; R1and R2are each independently a substituent; Z is C, P(Rp’), or S, wherein Rp’ is hydrogen or a substituent; X1is NR10, O, S, CH2, CH(Rx), or C(Rx)2; x is 1 or 2; Y3 is CH, C(Ry), or N; Lb is a single bond, a C1-C6 alkylene optionally substituted with at least one substituent, in which any carbon-carbon single bond of the C1-C6alkylene is optionally replaced by at leastPCT Application (NO137-703WO) one carbon-carbon double or triple bond, and any methylene of the C1-C6 alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Se, Ge, or Si; B is a 5-membered ring, 6-membered ring, a fused ring system thereof, or a bicyclic ring; the substituents each independently comprise: hydroxyl, deuterated hydroxyl, thiol, deuterated thiol, cyano, halogen, isonitrile (-NC), or nitro; or a C1-C12alkyl, a C2-C12alkenyl, a C2-C12alkynyl, a C3-C6cycloalkyl, a C1-C6alkyl(C3- C6 cycloalkyl), a C1-C6 alkyl(C3-C6 cycloalkenyl), a C3-C6 cycloalkenyl, a C2- C6 heterocycloalkyl, a C2-C6 heterocycloalkenyl, a C1-C6 alkyl(C2-C6 heterocycloalkyl), a C1- C6alkyl(C2-C6heterocycloalkenyl), a C5-C12aryl, C2-C30heteroaryl, a C1-C6alkyl (C5-C12aryl), or a C1-C6 alkyl (C2-C30 heteroaryl), optionally substituted with a deuterium, a halogen, or a combination thereof, wherein any carbon-carbon single bond of the C1-C12alkyl and the C1-C6alkyl is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of the C1-C12 alkyl and the C1-C6 alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), Se, Ge, or Si.

2. The compound of claim 1, wherein (a) m is 0, n is 1, and T is represented by T1 or T2; or (b) m is 1, n is 2 or 3, and T is represented by T1; or (c) m is 1, n is 2 or 3, and T is represented by T3.

3. The compound of claim 1, wherein m is 0, n is 1, and T is represented by T2.

4. The compound of claim 1, wherein m is 1, n is 1 or 2, and each occurrence of GT comprises represented by U or Y1’-U, wherein: U is hydroxyl (-OH), thiol (-SH), cyano (-CN), fluorine (-F), isonitrile (-NC), nitro (-NO2), -N=O(Y2’), NH2, -NH-Y2’, -N(Y2’)2, -O-Y2’, -S-Y2’, - S(=O)(Y2’), -S(=O)(Y2’)(NY2’), -S(=O)2(Y2’), aldehyde (–CH(=O)), -C(=O)Y2’, -C(=S)Y2’, -O- C(=O)Y2’,-O-C(=S)Y2’, -S-C(=O)Y2’, -S-C(=S)Y2’, -C(=O)-OY2’, -C(=S)Y2’, -C(=S)-OY2’, - C(=O)-SY2’, -C(=S)-SY2’, -O-C(=O)-OY2’, -O-C(=S)-OY2’, -O-C(=O)-SY2’, -O-C(=S)-SY2’, -S- C(=O)-OY2’, -S-C(=S)-OY2’, -S-C(=O)-SY2’, -S-C(=S)-SY2’,-C(=O)-NH2, -C(=O)-NH(Y2’), -PCT Application (NO137-703WO) C(=O)-N(Y2’)2, -C(=S)-NH2, -C(=S)-NH(Y2’), -C(=S)-N(Y2’)2, -NH-C(=O)-Y2’, -N(Y2’)-C(=O)- Y2’, -NH-C(=S)-Y2’, -N(Y2’)-C(=S)-Y2’, NH-S(=O)2-Y2’, N(Y2’)-(=O)2-Y2’, -O-C(=O)-NH2, -O- C(=O)-NH(Y2’), -O-C(=O)-N(Y2’)2, -O-C(=S)-NH2, -O-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, -NH- C(=O)-NH2, -NH-C(=O)-NH(Y2’), -NH-C(=O)-N(Y2’)2, -NH-C(=S)-NH2, -NH-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, -NH(Y2’)-C(=O)-NH2, -NH(Y2’)-C(=O)-NH(Y2’), -NH(Y2’)-C(=O)-N(Y2’)2, - NH(Y2’)-C(=S)-NH2, -NH(Y2’)-C(=S)-NH(Y2’), -O-C(=S)-N(Y2’)2, carboxylic acid (C(=O)OH), sulfonic acid (-SO3H), -C(=O)NH-NH2, -C(=S)NH-NH2, -S(=O)NH-NH2, -C(=O)NH-NH2, - C(=S)NH-NH2, or -C(=NH-NH2)Y2’; each occurrence of Y1’ and each occurrence of Y2’ independently comprise C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1- C3alkyl(C3-C6cycloalkyl), C1-C3alkyl(C3-C6cycloalkenyl), C3-C6cycloalkenyl, C2- C6 heterocycloalkyl, C2-C6 heterocycloalkenyl, C1-C3 alkyl(C2-C6 heterocycloalkyl), C1- C3 alkyl(C2-C6 heterocycloalkenyl), C5-C12 aryl, C2-C30 heteroaryl, C1-C6 alkyl (C2- C6heteroaryl), wherein U and Y1’-U are each optionally substituted with halogen, deuterium, or a combination thereof.

5. The compound of claim 1, wherein G is represented by one of Formulas G1 or G5; T is represented by Formula T1; and r1a and r2a are each 0.

6. The compound of claim 1, wherein G is represented by one of Formulas G2, G3, G6, or G7; T is represented by Formula T3; and the compound comprises selenium.

7. The compound of claim 1, wherein G is represented by Formula G4, wherein G’ is a bridged bicyclic ring system; or Formula G8, wherein G” is a bridged bicyclic ring system.

8. The compound of claim 1, wherein T is represented by one of Formulas (T1-1) to (T1-4) 3)PCT Application (NO137-703WO) .

9. The compound of claim 1, wherein T is represented by one of Formulas (T1-5) to (T1-8) 7)10. The compound of claim 1, wherein T is represented by Formula T2.

11. The compound of claim 1, wherein M comprises a transition metal or a rare earth metal; m is 0 or 1; n is 1, 2, or 3; wherein when m is 0, then n is 1, and when m is 1, then n is 2 or 3; G is represented by one of Formulas G1 to G8PCT Application (NO137-703WO) g"wherein: represents the attachment point between G1 to G8 to T; Z1-Z8are each independently C, P(Rp), or S; X1-X8are each independently N, O, S; X9a, X9b, X10a, X10b, X11a, X11b, X12a, X12b, X13a, X13b, X14a, X14b, X15a, X15b, X16a, and X16b, are each independently NR10 or O; Rxis a substituent; X1a and X2a are each independently NR10, O, or S; R10 is hydrogen or a substituent; r1a and r2a are each independently 0 or 1; Rpis hydrogen or a substituent; R2a and R2c are each independently hydrogen, deuterium, or a C1-C6 alkyl, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1- C6alkyl is optionally replaced by at least one carbon-carbon double or triple bond; W1-W12 are each independently hydrogen or a substituent; the moieties represented by V1-V2 and V3-V4 are each independently are each independently a C1-C6alkylene, optionally substituted with at least one substituent, wherein any carbon-carbon single bond of the C1-C6 alkylene is optionally replaced by at least one carbon- carbon double or triple bond, and any methylene is optionally replaced by at least one O, S, or NR10; G’ and G” are each independently a 5- to 6-membered ring, a bridged bicyclic ring system, or a fused ring system; Rg’and Rg”are each independently a substituent; g’ and g” are each independently 0 to 5; T is represented by one of Formula T1, T2, or T3PCT Application (NO137-703WO) 3)represents the attachment point between T1 to T3 and G; T1 is represented by one of Formulas T1-5 to T1-8 7)a or or a or a and b are each independently 0 to 5, Ra and Rb are each independently a substituent; R1and R2are each independently a substituent; Y3is CH, C(Ry), or N; Lb is a single bond, a C1-C6 alkylene optionally substituted with at least one substituent, in which any carbon-carbon single bond of the C1-C6 alkylene is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of the C1-C6alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), or Si; B is a 5-membered ring, 6-membered ring, a fused ring system thereof, or a bicyclic ring; the substituent and the at least one substituent each independently comprise:PCT Application (NO137-703WO) hydroxyl, deuterated hydroxyl, thiol, deuterated thiol, cyano, halogen, isonitrile (-NC), or nitro; or a C1-C12alkyl, a C2-C12alkenyl, a C2-C12alkynyl, a C3-C6cycloalkyl, a C1-C6alkyl(C3- C6 cycloalkyl), a C1-C6 alkyl(C3-C6 cycloalkenyl), a C3-C6 cycloalkenyl, a C2- C6 heterocycloalkyl, a C2-C6 heterocycloalkenyl, a C1-C6 alkyl(C2-C6 heterocycloalkyl), a C1- C6alkyl(C2-C6heterocycloalkenyl), a C5-C12aryl, C2-C30heteroaryl, a C1-C6alkyl (C5-C12aryl), or a C1-C6alkyl (C2-C30heteroaryl), optionally substituted with a deuterium, a halogen, or a combination thereof, wherein any carbon-carbon single bond of the C1-C12 alkyl and the C1-C6 alkyl is optionally replaced by at least one carbon-carbon double or triple bond, and any methylene of the C1-C12 alkyl and the C1-C6 alkyl is optionally replaced by at least one O, S, NR10, oxo (-C=O), imido (-C=NR10), thioxo (-C=S), or Si.

12. The compound of claim 1, wherein the compound is one of the following compoundsPCT Application (NO137-703WO)Se Se Se Se Se O NClNBr NN N N N N N N O O O O O O O O O OPCT Application (NO137-703WO)14. The pharmaceutical composition of claim 13, further comprising another cancer therapeutic.

15. A method for selectively inhibiting growth and / or inducing apoptosis of a tumor cell, comprising contacting the cell with an effective amount of the compound of claim 1.

16. A method for inhibiting coatomer protein complex subunit zeta 1 (COPZ1) in a cell, comprising contacting the cell with an effective amount of the compound of claim 1.

17. A method for inhibiting metastasis of a cancer cell, comprising contacting the cell with an effective amount of the compound of claim 1.

18. The method of claim 15, wherein the cell is a pancreatic cancer cell, a breast cancer cell, a melanoma cell, a lung cancer cell, a thyroid cancer cell, a glioblastoma cell, a cervical cancer cell, or a prostate cancer cell.

19. The method of claim 15, further comprising determining the expression of COPZ1 and / or COPZ2.

20. The method of claim 15, wherein the step of contacting the cell with the compound comprises administering the compound to the subject.

20. The method of claim 15, wherein the step of contacting the cell with the compound comprises administering the compound to the subject.

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