NVP-JDQ443 is a potent, mutant-selective, covalent KRAS G12C inhibitor;NVP-JDQ443 binds under the switch II loop with a novel binding mode, exploiting unique interactions with the KRAS G12C protein compared to sotorasib and adagrasib.NVP-JDQ443 potently inhibits KRASG12C cellular signaling and proliferation in a mutant selective manner.NVP-JDQ443 exhibits dose-dependent anti-tumor activity in mice bearing KRAS G12C mutated tumor xenografts comparable to sotorasib and adagrasib.NVP-JDQ443 is orally bioavailable and is well-tolerated.Combination of NVP-JDQ443 with the SHP2 inhibitor TNO155 further increases KRAS G12C target occupancy in vivo, enhanced pre-clinical anti-tumor activity, and delayed the emergence of resistance in xenografts.

THZ835 is a potent, mutant selective KRAS (G12D) inhibitor with IC50 of 1.6 uM;THZ835 binds to both GDP-bound and GMPPNP-bound KRAS G12D with similar affinities, efficiently disrupt KRAS–CRAF interaction, but do not bind to wide type and G12C mutant KRAS.TH-Z835 reduced the pERK level in PANC-1 cells with an IC50 <2.5 uM, exhibited anti-proliferative effects for KRAS(G12D)-bearing pancreatic cancer cell lines PANC-1 and KPC with IC50 of <0.5 uM, induced arrest at the G1 phase of the cell cycle.TH-Z835 displayed anti-tumor effects alone and in combination with anti-PD-L1 antibody in xenograft pancreatic tumor models.

MRTX-0902 is a highly potent, selective SOS1 inhibitor with binding IC50 of 2 nM, cellular IC50 of 33 nM (pERK);MRTX-0902 displays weak to no affinity for SOS2 with IC50 of >10 uM.MRTX-0902 exhibits promising potency, selectivity, and exposure in preclinical species.MRTX-0902 in combined with MRTX849 demonstrates durable regression in KRasG12C NSCLC and CRC PDX models.MRTX-0902 demonstrates improved efficacy with osimertinib (EGFRi), VS-6766 (RAF/MEKc) in MAPK tumor models.

Garsorasib is a potent inhibitor of KRAS G12C with IC50 of 10 nM; Garsorasib has the potential for the research of various cancer such as pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer (non-small cell lung cancer)

RMC-0331 (RM-023) is a potent, selective and orally bioavailable SOS1 inhibitor. RMC-0331 is an in vivo tool compound that blocks RAS activation via disruption of the RAS-SOS1 interaction;RMC-0331 has an IC50 of 71 nM measuring by the rate of GDP/GTP exchange in vitro.

Sotorasib(AMG-510) is a first-in-class, orally bioavailable, and selective KRAS G12C covalent inhibitor. AMG-510 irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state. AMG-510 is the first KRAS G12C inhibitor in clinical development and leads to the regression of KRAS G12C tumors.

MRTX849 is a potent, orally-available, and mutation-selective covalent inhibitor of KRAS G12C with potential antineoplastic activity; MRTX849 covalently binds to KRAS G12C at the cysteine at residue 12, locks the protein in its inactive GDP-bound conformation, and inhibits KRAS-dependent signal transduction.

A small molecule inhibitor of guanine nucleotide exchange factor (GEF) catalytic activity that binds to SOS1 (Kd=14.7 uM) and disrupts GEF-Ras interaction; dose-dependently disrupts the SOS1-Ras interaction by competitively inhibiting the binding of SOS1cat to GDP-bound H-Ras in a microscale thermophoresis assay; dose-dependently inhibits Ras activation and downstream ERK activation mediated through EGFR-SOS1-Ras-Raf1-MEK-ERK signaling, specifically inhibits wild-type mouse embryonic fibroblast growth but not the growth of oncogenic H-Ras(G12V)-expressing mouse embryonic fibroblasts; inhibits Ras signaling and growth of pancreatic and prostate cancer cells.

A small molecule inhibitor of guanine nucleotide exchange factor (GEF) catalytic activity that binds to SOS1 (Kd=3.4 uM) and disrupts GEF-Ras interaction; dose-dependently disrupts the SOS1-Ras interaction by competitively inhibiting the binding of SOS1cat to GDP-bound H-Ras in a microscale thermophoresis assay; dose-dependently inhibits Ras activation and downstream ERK activation mediated through EGFR-SOS1-Ras-Raf1-MEK-ERK signaling, specifically inhibits wild-type mouse embryonic fibroblast growth but not the growth of oncogenic H-Ras(G12V)-expressing mouse embryonic fibroblasts; inhibits Ras signaling and growth of pancreatic and prostate cancer cells.

A novel semisynthetic derivative of andrographolide that directly target Ras to block the exchange of GDP for GTP and thus prevent Ras activation; significantly suppresses K-Ras GTP loading, whereas H-Ras and N-Ras GTP loading are much less sensitive; reduceds K-RasG12V GTP, phosphorylated ERK (ppERK) levels in K-RasG12V-transformed cells; induces G1 arrest and apoptosis in MCF-7 and HCT-116 cells, respectively.