RMC-9805

RMC-9805
Clinical data
Drug class	Antineoplastic agents
Identifiers
	IUPAC name (2S)-2-Cyclopentyl-2-[(5S)-7-{[(2R,3R)-3-cyclopropyl-1-methyl-2-aziridinyl]carbonyl}-2,7-diazaspiro[4.4]non-2-yl]-N-[(6S,8S,14S)-21-{5-(4-cyclopropyl-1-piperazinyl)-2-[(1S)-1-methoxyethyl]-3-pyridinyl }-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-5,16-dioxa-2,10,22,28-tetraazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(25),20,23,26-tetraen-8-yl]acetamide;
CAS Number	2922732-54-3;
PubChem CID	168201327;
ChemSpider	128942583;
Chemical and physical data
Formula	C63H88F3N11O7
Molar mass	1168.462 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(N1CCC[C@@H]2N1)[C@H](C[C@@H](C3)OCCN3C4=CC5=C(N(CC(F)(F)F)[C@]([C@]6=C([C@H](C)OC)N=CC(N7CCN(C8CC8)CC7)=C6)=C5CC(C)(C)COC2=O)C=C4)NC([C@@H](N9C[C@]%10(CN(C([C@@H]%11N(C)[C@@H]%11C%12CC%12)=O)CC%10)CC9)C%13CCCC%13)=O;
	InChI InChI=InChI=1S/C63H88F3N11O7/c1-39(82-5)52-47(30-44(33-67-52)72-25-23-71(24-26-72)42-14-15-42)55-48-32-61(2,3)38-84-60(81)49-11-8-20-77(69-49)58(79)50(31-45-34-73(27-28-83-45)43-16-17-51(46(48)29-43)76(55)37-63(64,65)66)68-57(78)54(40-9-6-7-10-40)74-21-18-62(35-74)19-22-75(36-62)59(80)56-53(70(56)4)41-12-13-41/h16-17,29-30,33,39-42,45,49-50,53-54,56,69H,6-15,18-28,31-32,34-38H2,1-5H3,(H,68,78)/t39?,45-,49-,50-,53+,54-,56+,62-,70?/m0/s1; Key:VKNNQJWNUPSOEK-QFVODIEJSA-N;

RMC-9805 is an investigational drug that selectively targets the G12D mutation in KRAS dependent cancers.^[1]^[2]^[3] RMC-9805 functions as molecular glue that forms a non-covalent ligand-mediated protein-protein interaction between cyclophilin A and GTP-bound RAS. Subsequent covalent modification of the mutant Asp12 residue affords selectivity over wild-type RAS.^[4]^[5]

RMC-9805 is currently in a phase 1/1b clinical trial for the treatment of KRAS G12D-mutant solid tumors.^[6] Preliminary data indicated that KRAS G12D–mutant PDAC patients dosed at 1200 mg daily or 600 mg twice daily achieved a 30% objective response rate (n = 12) and 80% disease control rate (n = 32).^[7]

References

^ "RMC-9805". AdisInsight. Springer Nature Switzerland AG.
^ "KRAS G12D inhibitor RMC-9805". NCI Drug Dictionary. National Cancer Institute. Retrieved 2024-12-03.
^ Zeissig MN, Ashwood LM, Kondrashova O, Sutherland KD (November 2023). "Next batter up! Targeting cancers with KRAS-G12D mutations". Trends in Cancer. 9 (11): 955–967. doi:10.1016/j.trecan.2023.07.010. PMID 37591766.
^ de Jesus VH, Mathias-Machado MC, de Farias JP, Aruquipa MP, Jácome AA, Peixoto RD (October 2023). "Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure". Cancers. 15 (20): 5015. doi:10.3390/cancers15205015. PMC 10605759. PMID 37894382.
^ Bannoura SF, Khan HY, Azmi AS (November 2022). "KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered?". Frontiers in Oncology. 12: 1–9. doi:10.3389/fonc.2022.1013902. PMC 9749787. PMID 36531078.
^ Clinical trial number NCT06040541 for "Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors" at ClinicalTrials.gov
^ Seymour C (2024-10-28). "RMC-9805 Triggers Tumor Regressions in KRAS G12D–Mutant Pancreatic Cancer". OncLive. Retrieved 2024-12-03.

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[1] "RMC-9805". AdisInsight. Springer Nature Switzerland AG.

[2] "KRAS G12D inhibitor RMC-9805". NCI Drug Dictionary. National Cancer Institute. Retrieved 2024-12-03.

[Zeissig_2023-3] Zeissig MN, Ashwood LM, Kondrashova O, Sutherland KD (November 2023). "Next batter up! Targeting cancers with KRAS-G12D mutations". Trends in Cancer. 9 (11): 955–967. doi:10.1016/j.trecan.2023.07.010. PMID 37591766.

[deJesus_2023-4] Jesus VH, Mathias-Machado MC, de Farias JP, Aruquipa MP, Jácome AA, Peixoto RD (October 2023). "Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure". Cancers. 15 (20): 5015. doi:10.3390/cancers15205015. PMC 10605759. PMID 37894382.

[Bannoura_2022-5] Bannoura SF, Khan HY, Azmi AS (November 2022). "KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered?". Frontiers in Oncology. 12: 1–9. doi:10.3389/fonc.2022.1013902. PMC 9749787. PMID 36531078.

[6] Clinical trial number NCT06040541 for "Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors" at ClinicalTrials.gov

[7] Seymour C (2024-10-28). "RMC-9805 Triggers Tumor Regressions in KRAS G12D–Mutant Pancreatic Cancer". OncLive. Retrieved 2024-12-03.

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See also

References