SOS1-IN-11 is a potent SOS1 inhibitor with an IC50 value of 30 nM.

MRTX0902 is a potent SOS1 inhibitor with an IC50 of 46 nM (WO2021127429A1; Example 12-10).

KRAS G12C inhibitor 34 is a KRAS G12C inhibitor extracted from patent WO2021239058A1, compound Z1. KRAS G12C inhibitor 34 can be used for the research of cancer.

SOS1-IN-6 (compound 33-P1) is a potent SOS1 inhibitor with IC50s of 14.9 and 73.3 nM for SOS1-G12D and SOS1-G12V, respectively.

KRAS G12C inhibitor 31 is a KRAS G12C inhibitor extracted from patent WO2021252339A1, compound 1. KRAS G12C inhibitor 31 can be used for the research of cancer.

KRAS G12C inhibitor 30 is a KRAS G12C inhibitor extracted from patent WO2021252339A1, compound 2. KRAS G12C inhibitor 30 can be used for the research of cancer.

SOS1-IN-7 (compound 18-p1) is a potent SOS1 inhibitor with IC50s of 20 and 67 nM for SOS1-G12D and SOS1-G12V, respectively.

KRAS G12D inhibitor 3 is a KRAS G12D inhibitor with an IC50 of <500 nM. KRAS G12D inhibitor 3 has antitumor effects (WO2022002102A1; compound 146).

KRAS G12D inhibitor 3 TFA is a KRAS G12D inhibitor with an IC50 of <500 nM. KRAS G12D inhibitor 3 TFA has antitumor effects (WO2022002102A1; compound 146).

SOS1-IN-8 is a potent SOS1 inhibitor with IC50s of 11.6 and 40.7 nM for SOS1-G12D and SOS1-G12V, respectively (WO2022017339A1, compound 2).

AZD4625 is a potent, selective, covalent allosteric inhibitor of mutant GTPase KRAS G12C with IC50 of 3 nM, inhibitor H358 cell proliferation with GI50 of 4 nM.AZD4625 is a clinical development candidate for the treatment of KRASG12C positive tumors.

DW0254 (DW-0254,DW 0254) is a small molecules capable of inhibiting RAS-related C3 botulinum toxin substrate (RAC) small GTPase activation in ALL cell lines, directly binds to the hydrophobic pocket of PDE6D (Kd=436 nM, ITC), a RAS chaperone protein.DW0254 demonstrated dose-dependent RAC inhibition, arrest of proliferation and induced apoptosis in human leukemic cell lines (RS4;11 IC50=1.5-1.8 uM), also showed promising anti-leukemic activity in RAS-mutated cells (CCRF-CEM NRAS G12D, IC50=3.3-4.2 uM).DW0254 disrupted the interaction between PDE6D and RAS, disturbing RAS subcellular localization.DW0254 demonstrated anti-leukemic activity, decreased tumor progression in a murine xenograft model.

IODVA1 is a small molecule with cellular inhibitory activity against several transformed cell lines including Ras-driven cells, targets Rac activation and signaling instead of Ras; IODVA1 inhibits ST8814 cell proliferation with GI50 of 1 uM, similar results were observed with MCF7, MDA-MB-231, and T47D cells with estimated GI50s <1 uM. IODVA1 significantly decreases number of colonies of the breast cancer cells in soft agar at 1 and 3 uM. IODVA1 probably does not bind Ras and that its mechanism of action is likely Ras-independent, inhibits lamellipodia and circular dorsal ruffle (CDR) formation in MDA-MB-231 cells and decreases Rac activation. IODVA1 inhibits Rac activation and downstream signaling leading to inhibition of lamellipodia and CDR formation; IODVA1 inhibits cell-substratum and cell-cell interactions, does not target kinases, and reduces tumor burden of solid tumors in vivo.

KAL-21404358 (KAL21404358) is a small-molecule, allosteric inhibitor of K-Ras(G12D), binds to K-Ras(G12D) P110 site with KD of 88 uM in MST assay; KAL-21404358 disrupts the K-RasG12D-B-Raf interaction using a NanoBiT split luciferase assay, and to impair the Raf-MEK-ERK and the PI3K-AKT signaling pathways. KAL-21404358 exhibited specificity for K-RasG12D over K-RasWT, H-RasWT, Rap1a, R-Ras and R-Ras2.

KRAS G12C Pipetide (LVVVGACGVGK)

K-Ras G12D inhibitor KS-58 is the first K-Ras(G12D) selective, bicyclic peptide inhibitor with binding Ki of 22 nM; KS-58 suppressed growth of A427 cells and PANC-1 cells (human pancreas carcinoma, G12D mutant) down to 21.1% and 50.1% at 30 uM. KS-58 showed significantly weaker cell growth suppression activities against A549 (human lung carcinoma, G12S mutant), H1975 (human lung carcinoma, WT), MIA PaCa-2 (human pancreas carcinoma, G12C mutant), and Capan-1 (human pancreas carcinoma, G12V mutant) cells. KS-58 reduced the phosphorylation of ERK down to 26.0% and 57.6% at 30 uM, respectively. Biotin-KS-58 exhibited stronger binding to K-Ras(G12D) than to other Ras proteins; KS-58 enters cells, binds to both forms of intracellular K-Ras(G12D)GDP/GTP, and inhibits K-Ras(G12D)GDP/GTP-effector protein interactions, thus preventing downstream Ras signal pathways, such as ERK, and suppressing cell proliferation. KS-58 exhibits anti-cancer activity when given as an intravenous injection to mice with subcutaneous or orthotropic PANC-1 cell xenografts.

KRpep-2d (Ac-RRCPLYISYDPVCRR-NH2) is a potent, selective, cell-membrane permeable, cyclic peptide inhibitor of K-Ras(G12D) with IC50 of 1.6 nM, >10-fold selectivity over WT and G12C KRas; KRpep-2d significantly suppressed ERK-phosphorylation, downstream of K-Ras(G12D), along with A427 cancer cell proliferation at 30 μM peptide concentration.

K-tetracosapeptide (K-TC) is a peptide of 24 amino acids corresponding to the helix a5 in KRAS4B, potent inhibitor of KARATE (KRAS4B-RHOA-mTORC2 Ensemble), specifically targets the KRAS4B-RHOA interaction.

LY-3537982 (LY3537982) is a highly selective and potent KRAS-G12C inhibitor, selectively inhibits growth of KRAS G12C mutant cells (IC50=1-60 nM).LY-3537982 does not inhibit growth of KRAS G12S/G13C/G12D mutant cells and WT KRAS cells (CI50>10 uM).LY-3537982 displays high selectivity for proteome-wide cysteine residues was evaluated using competitive chemical proteomics (8866 peptides).LY3537982 inhibits the growth of subcutaneous EL3187 NSCLC PDX tumors in nude mice in a dose dependent manner.LY3537982 demonstrates robust tumor regression in combination with other agents in KRAS G12C in vivo models.LY3537982 is a promising KRAS G12C inhibitor predicted to deliver >90% KRAS G12C target occupancy in the clinic.

MRTX-EX185 (EX185) is a novel potent small-molecule inhibitor of KRAS mutants, exhibits target engagement against KRAS(G12D) with IC50 of 90 nM, binds to GDP-loaded KRAS and KRAS(G12D), as well as the active GNP state.MRTX-EX185 also bound GDP-loaded HRAS.MRTX-EX185 engages both nucleotide states-albeit with preference for the inactive GDP-loaded protein-and might present an opportunity to inhibit even constitutively active (GTP-loaded) KRAS hotspot mutants MRTX-EX185 engages numerous KRAS Q61, G12 and G13 mutant proteins and drives antiproliferation.

NSC290956 is a small molecule inhibitor of KRas with Kd of 21.3 uM.NSC290956 inhibits KRas activity and downstream signaling events in KRas-driven nuytant NSCLC cells, decreases the cellular viability, cell cycle, and migration.NSC290956 changes KRas-dependent metabolic phenotype in Non-small-cell lung cancer cells, regulates mitochondrial dysfunction for apoptosis in both A549 and H358 cells.NSC290956 shows activity in the KRas mutant cell line xenograft.

PHT-7.3 (Cnksr1 (Cnk1) inhibitor PHT-7.3) is a selective inhibitor of connector enhancer of kinase suppressor of Ras 1 (Cnk1) pleckstrin homology (PH) domain (Kd=4.7 μM).PHT-7.3 bound selectively to the PH domain of Cnk1, preventing plasma membrane colocalization with mut-KRas.PHT-7.3 inhibits mut-KRas, but not wild-type KRas cancer cell and tumor growth and signaling.