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Ras inhibitors and related small GTPase modulators act on KRAS and on the Rac, Rho and Cdc42 proteins. Small GTPases of the Ras superfamily work as molecular switches. They cycle between an active form bound to guanosine triphosphate (GTP) and an inactive form bound to guanosine diphosphate (GDP). Oncogenic KRAS mutations such as G12C keep the protein in its signaling state. ARS-853 and KRas G12C inhibitor 4 target the mutant cysteine of KRAS G12C, while Kobe2602 interferes with binding of Ras to Raf. Salirasib, a farnesylcysteine mimetic, disrupts the membrane association of Ras. Rho-family tools include NSC 23766 and EHT 1864, which inhibit Rac, and CASIN, which targets Cdc42.
Synonyms: IBI351; GFH925
Fulzerasib (GFH925) is an irreversible inhibitor of KRAS^G12C, demonstrating potent anticancer activity. It exhibits synergistic effects when combined with cetuximab, enhancing the therapeutic efficacy against KRAS^G12C-driven tumors.
AZA197 is a selective small molecule inhibitor of Cdc42 that suppresses colon cancer cell proliferation, migration, and invasion, while promoting apoptosis. Its mechanism involves downregulation of the PAK1 and ERK signaling pathways. In vivo, AZA197 significantly reduces tumor growth and improves survival in SW620 xenograft mouse models, highlighting its potential for cancer research and therapy.
ADT-007 is a potent and orally active pan-RAS inhibitor with strong anticancer activity. It binds to RAS in its nucleotide-free conformation, effectively blocking GTP loading and activation. ADT-007 selectively inhibits the proliferation of cancer cells harboring mutated or hyperactivated wild-type RAS isozymes, making it a promising candidate for RAS-driven cancer research and therapy.
TH-Z816 is a reversible inhibitor targeting the KRAS^G12D mutation, with an IC50 value of 14 μM. It is a useful tool for cancer research, particularly in studies involving KRAS^G12D-driven tumorigenesis.
MRTX1133 is a noncovalent, potent, and selective KRAS G12D inhibitor featuring an alkyne-based structure. It binds with high affinity to the switch II pocket of KRAS G12D, with an estimated KD of 0.2 pM, engaging three key substituents that enhance protein interactions. MRTX1133 inhibits SOS1-mediated nucleotide exchange and disrupts formation of the KRAS G12D/GTP/RAF1 complex, thereby blocking downstream mutant KRAS signaling. It selectively targets KRAS G12D mutant cells without affecting KRAS wild-type cells, exhibiting single-digit nanomolar potency in cellular assays and strong antitumor efficacy in KRAS G12D-driven in vivo models.
Ibetazol is an importin β1 (KPNB1) inhibitor that covalently binds to Cys585 of importin β1, thereby blocking importin β1-mediated nuclear import. It exhibits an EC₅₀ of 6.1 µM in cellular assays.
RMC-5127 is an orally active, brain-penetrant, mutant-selective tri-complex inhibitor targeting RASG12V. It non-covalently binds to cyclophilin A (CypA), forming a binary complex that engages active RASG12V to create a high-affinity tri-complex, thereby sterically blocking RAS-effector interactions. RMC-5127 inhibits RAS signaling in KRASG12V-mutant cancer cells, suppressing proliferation and inducing apoptosis. It holds promise for the study of RAS-mutant cancers, including non-small cell lung cancer.
BI-2493 is a structural analogue of BI-2865 and functions as a highly selective, orally active pan-KRAS inhibitor. It effectively suppresses tumor growth and is suitable for research in KRAS-driven cancers.
Manumycin A is a polyketide antibiotic that functions as an inhibitor of thioredoxin reductase 1 (TrxR-1). It exhibits anti-tumor activity by inhibiting breast cancer cell growth, potentially through LC3-mediated mechanisms. Manumycin A also downregulates pro-inflammatory cytokine release in TNF-α-stimulated human monocytes, indicating anti-inflammatory potential. Additionally, it inhibits the Ras/Raf/ERK1/2 signaling pathway and hnRNP H1 in castration-resistant prostate cancer cells, thereby suppressing exosome biogenesis and secretion.
DCC-3116 is an orally active inhibitor of ULK1/2 that suppresses autophagy in lung cancer cells. By targeting ULK1/2, DCC-3116 inhibits KRAS^G12C-driven signaling pathways, leading to reduced cell proliferation and demonstrating anti-tumor activity in KRAS-mutant lung cancer models.
MRTX0902 is an orally active and potent SOS1 inhibitor, exhibiting an IC₅₀ of 46 nM (WO2021127429A1; Example 12-10). It is designed to disrupt the SOS1–KRAS interaction, making it a promising candidate for targeting KRAS-driven cancers.
Synonyms: NVP-JDQ443; JDQ-443
Opnurasib (JDQ-443, also known as NVP-JDQ443) is an orally active, potent, selective, and covalent KRAS^G12C inhibitor, as described in patent WO2021120890A1. It exhibits strong antitumor activity in KRAS^G12C-driven cancer models.
BI-2852 is a KRAS inhibitor designed to target the switch I/II (SI/II) pocket with nanomolar affinity. Unlike covalent KRAS^G12C inhibitors that bind the switch II pocket, BI-2852 exhibits a distinct mechanism of action and binds preferentially to active KRAS^G12D with \~10-fold greater affinity than KRAS^WT (740 nM vs. 7.5 μM). It disrupts interactions between KRAS and GEFs, GAPs, and effectors, thereby inhibiting downstream signaling and exerting antiproliferative effects in KRAS-mutant cells.
Synonyms: GDC-6036
Divarasib (GDC-6036) is an orally bioavailable, highly potent, and selective KRAS^G12C inhibitor with an IC₅₀ of
AMG410 is a non-covalent, selective pan-KRAS inhibitor with IC₅₀ values of 1–4 nM against KRAS^G12D, KRAS^G12V, and KRAS^G13D. It demonstrates over 100-fold selectivity against HRAS and NRAS. AMG410 functions as a dual-state inhibitor, binding both GDP-bound (K\_d = 1 nM) and GTP-bound (K\_d = 22 nM) KRAS, effectively blocking signaling independent of the nucleotide state. It also inhibits proliferation in wild-type KRAS-amplified tumor cells and is suitable for research in colorectal, pancreatic, and lung cancers.
BI-2865 is a non-covalent pan-KRAS inhibitor that binds to wild-type and mutant KRAS variants, including G12C, G12D, G12V, and G13D, with dissociation constants (K\_D) of 6.9, 4.5, 32, 26, and 4.3 nM, respectively. It inhibits the proliferation of Ba/F3 cells expressing KRAS^G12C, KRAS^G12D, or KRAS^G12V, with a mean IC₅₀ of approximately 140 nM.
Synonyms: RAS-IN-2; RMC-6236
Daraxonrasib (RMC-6236) is an orally active, non-covalent RAS(ON) inhibitor that disrupts the interaction between wild-type or mutant RAS proteins and the RAS-binding domain of BRAF. It exhibits EC₅₀ values ranging from 28 to 220 nM across wild-type KRAS, NRAS, HRAS, and multiple oncogenic RAS variants. RMC-6236 inhibits pERK signaling and demonstrates anti-tumor activity in KRAS-mutant tumor models.
HRS-4642 is a selective KRAS^G12D inhibitor with a dissociation constant (Kd) of 0.083 nM, demonstrating potent anti-cancer activity. It synergizes with Carfilzomib and exhibits strong in vivo efficacy, promoting remodeling of the tumor microenvironment into an immune-activating state.
AZD4625 (Compound 21) is a highly potent, selective, covalent, and allosteric inhibitor of the mutant GTPase KRAS^G12C. It exhibits strong target engagement and high oral bioavailability, making it a promising candidate for the treatment of KRAS^G12C-driven cancers.
SCH 51344 is a small molecule inhibitor that suppresses Ras-induced malignant transformation and inhibits anchorage-independent growth of oncogene-transformed fibroblasts. It is used in research to study Ras-driven oncogenic signaling and cellular transformation.
CCG-232601 (compound 8f) is a potent and orally active inhibitor of the Rho/MRTF/SRF transcriptional pathway. It effectively inhibits the development of bleomycin-induced dermal fibrosis in mice and holds potential for antifibrotic research in systemic scleroderma and related fibrotic disorders.
TH-Z835 is a mutant-selective KRAS^G12D inhibitor with an IC₅₀ of 1.6 μM. It inhibits both mantGMPPNP/GPPNP and GPPNP/mantGMPPNP nucleotide exchange, effectively targeting KRAS^G12D activation and signaling.
SOS1-IN-11 is a potent small-molecule inhibitor of SOS1, exhibiting an IC₅₀ value of 30 nM. It is used in research to disrupt the SOS1–KRAS interaction and modulate RAS signaling pathways in cancer models.
Synonyms: D3S-001
Elisrasib (D3S-001) is an orally active KRAS^G12C inhibitor that potently inhibits the proliferation of KRAS^G12C-mutant H358 and MIA PaCa-2 cells, with IC₅₀ values of 0.6 nM and 0.44 nM, respectively. It demonstrates good metabolic stability in hepatocytes, liver microsomes, plasma, and whole blood across multiple species. Elisrasib also exhibits favorable pharmacokinetic properties and significant antitumor efficacy in mouse models.
AZD4747 is a potent and selective covalent inhibitor of the mutant GTPase KRASG12C. It exhibits excellent blood–brain barrier permeability and demonstrates strong antitumor potential in preclinical models of pancreatic and colorectal adenocarcinoma. By irreversibly binding to the cysteine residue within the KRASG12C mutant, AZD4747 effectively suppresses downstream MAPK signaling, leading to inhibition of tumor cell proliferation and survival.
