RMC-7977 | CAS#2765082-12-8 | RAS inhibitor

MedKoo Cat#: 207204 | Name: RMC-7977

Description:

WARNING: This product is for research use only, not for human or veterinary use.

RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS oncoproteins (RAS MULTI) and is a preclinical tool compound representative of the clinical candidate RMC-6236. RMC-7977 suppressed cell proliferation in AML cell lines driven by FLT3-ITD (Molm-14, MV4-11), KITN822K (Kasumi-1, SKNO-1) and RAS mutations ( NRASQ61L -OCIAML-3, HL-60, KRASG13D - NOMO-1) with IC 50 values between 5 and 33 nM and repressed phosphorylation of downstream effectors of the MAPK pathway MEK, ERK and RSK. RMC-7977 induced apoptosis, but to different extents across AML cell lines. RMC-7977 and venetoclax showed high synergistic activity as assessed by Bliss independence model.

Chemical Structure

RMC-7977

CAS#2765082-12-8

Theoretical Analysis

MedKoo Cat#: 207204

Name: RMC-7977

CAS#: 2765082-12-8

Chemical Formula: C47H60N8O6S

Exact Mass: 864.4357

Molecular Weight: 865.11

Elemental Analysis: C, 65.25; H, 6.99; N, 12.95; O, 11.10; S, 3.71

Price and Availability

Size	Price	Availability
1mg	USD 90.00	Ready to Ship
5mg	USD 350.00	Ready to Ship
10mg	USD 550.00	Ready to Ship
25mg	USD 950.00	Ready to Ship
50mg	USD 1,650.00	Ready to Ship
100mg	USD 2,650.00	Ready to Ship
200mg	USD 4,650.00	Ready to Ship

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Related CAS #

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Synonym

RMC-7977; RMC 7977; RMC7977;

IUPAC/Chemical Name

(1R,5S,6r)-N-((63S,4R,Z)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

InChi Key

NBLZKEHVVJSAAY-OFTZCYAMSA-N

InChi Code

InChI=1S/C47H60N8O6S/c1-6-54-39-12-9-28-18-31(39)33(43(54)32-19-30(22-48-42(32)27(2)59-5)53-16-14-52(15-17-53)29-10-11-29)21-47(3,4)26-61-46(58)36-8-7-13-55(51-36)45(57)37(20-40-49-38(28)25-62-40)50-44(56)41-34-23-60-24-35(34)41/h9,12,18-19,22,25,27,29,34-37,41,51H,6-8,10-11,13-17,20-21,23-24,26H2,1-5H3,(H,50,56)/t27-,34-,35+,36-,37+,41+/m0/s1

SMILES Code

CO[C@H](C1=[C@@](C=C(N2CCN(C3CC3)CC2)C=N1)[C@@](N4CC)=C(C5=C4C=CC6=C5)CC(C)(C)COC([C@@H](N7)CCCN7C([C@@H](NC([C@@H]8[C@@H]9[C@H]8COC9)=O)CC%10=NC6=CS%10)=O)=O)C

Appearance

To be determined

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 -4 C for short term (days to weeks) or -20 C for long term(months to years).

Solubility

To be determined

Shelf Life

>2 years if stored properly

Drug Formulation

To be determined

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

FLT3 inhibitors (FLT3i) such as gilteritinib are clinically active in AML, but their use is limited by resistance due to emergence of clones with RAS/MAPK mutations, both alone and in combination with FLT3 mutations, or with other drivers such as KIT mutations. RAS mutations are also commonly associated with relapse on IDH1/2 inhibitors and the BCL2 inhibitor venetoclax. Importantly, multiple heterogeneous resistant clones are identified at the time of relapse. In addition, 5-10% of all de novo patients harbor oncogenic RAS mutations. Patients with RAS mutations or other mutations that activate RAS/MAPK signaling do not benefit from clinically approved targeted therapies. Targeting oncogenic RAS has been historically challenging and inhibition of downstream effectors of the MAPK pathway, such as MEK, demonstrated modest activity and high toxicity in clinical trials. Effective inhibition of the RAS/MAPK pathway is therefore a critical unmet need in AML. RMC-7977 non-covalently binds to the intracellular chaperone cyclophilin A, generating a neomorphic interface with high affinity for all isoforms of RAS. The resulting tri-complexes sterically block RAS-effector interactions required for propagating oncogenic signals.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A24T05K15

QC Data

View QC data: current batch, Lot#A24T05K15

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

RMC-7977 is a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JAM, Wildes D, Singh M. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature. 2024 May;629(8013):919-926. doi: 10.1038/s41586-024-07205-6. Epub 2024 Apr 8. PMID: 38589574; PMCID: PMC11111408.

In vitro activity:

In an in vitro study, RMC-7977, a reversible RAS inhibitor, demonstrated potent activity against various RAS-addicted tumors, including those with KRAS codon 12 mutations. 1. Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JAM, Wildes D, Singh M. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature. 2024 May;629(8013):919-926. doi: 10.1038/s41586-024-07205-6. Epub 2024 Apr 8. PMID: 38589574; PMCID: PMC11111408.

In vivo activity:

In an in vivo study, RMC-7977, a highly selective inhibitor of active RAS variants, showed significant anti-tumor activity in pancreatic ductal adenocarcinoma (PDAC) models driven by KRAS mutations. 1. Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, Lee B, Orlen M, Tian S, Stalnecker CA, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Muonio K, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs WP, Hibshman PS, Amparo AM, Hennessey C, Rees MG, Ronan MM, Roth JA, Brodbeck J, Tomassoni L, Bakir B, Socci ND, Herring LE, Barker NK, Wang J, Cleary JM, Wolpin BM, Chabot JA, Kluger MD, Manji GA, Tsai KY, Sekulic M, Lagana SM, Califano A, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Lowe SW, Badgley MA, Aguirre AJ, Vonderheide RH, Stanger BZ, Baslan T, Der CJ, Singh M, Olive KP. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature. 2024 May;629(8013):927-936. doi: 10.1038/s41586-024-07379-z. Epub 2024 Apr 8. PMID: 38588697; PMCID: PMC11111406.

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	125.0	144.49

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 865.11 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JAM, Wildes D, Singh M. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature. 2024 May;629(8013):919-926. doi: 10.1038/s41586-024-07205-6. Epub 2024 Apr 8. PMID: 38589574; PMCID: PMC11111408. Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, Lee B, Orlen M, Tian S, Stalnecker CA, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Muonio K, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs WP, Hibshman PS, Amparo AM, Hennessey C, Rees MG, Ronan MM, Roth JA, Brodbeck J, Tomassoni L, Bakir B, Socci ND, Herring LE, Barker NK, Wang J, Cleary JM, Wolpin BM, Chabot JA, Kluger MD, Manji GA, Tsai KY, Sekulic M, Lagana SM, Califano A, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Lowe SW, Badgley MA, Aguirre AJ, Vonderheide RH, Stanger BZ, Baslan T, Der CJ, Singh M, Olive KP. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature. 2024 May;629(8013):927-936. doi: 10.1038/s41586-024-07379-z. Epub 2024 Apr 8. PMID: 38588697; PMCID: PMC11111406.

In vitro protocol:

In vivo protocol:

Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, Lee B, Orlen M, Tian S, Stalnecker CA, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Muonio K, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs WP, Hibshman PS, Amparo AM, Hennessey C, Rees MG, Ronan MM, Roth JA, Brodbeck J, Tomassoni L, Bakir B, Socci ND, Herring LE, Barker NK, Wang J, Cleary JM, Wolpin BM, Chabot JA, Kluger MD, Manji GA, Tsai KY, Sekulic M, Lagana SM, Califano A, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Lowe SW, Badgley MA, Aguirre AJ, Vonderheide RH, Stanger BZ, Baslan T, Der CJ, Singh M, Olive KP. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature. 2024 May;629(8013):927-936. doi: 10.1038/s41586-024-07379-z. Epub 2024 Apr 8. PMID: 38588697; PMCID: PMC11111406.

https://ashpublications.org/blood/article/142/Supplement%201/2793/499451/RAS-MULTI-ON-Inhibitor-RMC-7977-Targets-Oncogenic 1. Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JAM, Wildes D, Singh M. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature. 2024 May;629(8013):919-926. doi: 10.1038/s41586-024-07205-6. Epub 2024 Apr 8. PMID: 38589574; PMCID: PMC11111408. 2. Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JAM, Wildes D, Singh M. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature. 2024 May;629(8013):919-926. doi: 10.1038/s41586-024-07205-6. Epub 2024 Apr 8. PMID: 38589574; PMCID: PMC11111408.