Ral inhibitor 1 is a covalent inhibitor of RalB (Ras-like GTPase) activation, inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase, selectively inhibits Ral over Ras; Ral inhibitor 1 inhibits RalB/Rgl2 interaction through covalent reaction at Tyr-82 with IC50 of 49.5 uM; Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases.

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.

PF-07284890 (ARRY-461) is an orally bioavailable, brain penetrant, potent, small molecule BRAF V600 mutants inhibitor, inhibits BRAF and CRAF with IC50 of 5.8 and 4.1 nM, respectively.PF-07284890 inhibits the clinically relevant kinase domain BRAF V600 mutants (V600E and V600K) with IC50 of 24-25 nM.PF-07284890 potently inhibits phosphorylation of ERK, a downstream marker of BRAF inhibition, and potently inhibits proliferation of BRAF V600E/K mutant melanoma cell lines (IC50=18-38 nM).PF-07284890 inhibits phosphorylation of ERK in A375 BRAF V600E tumors, achieving maximal target inhibitions at a dose of 10 mg/kg.PF-07284890 (10-30 mg/kg BID) caused significant and durable tumor regressions in the intracranial A375-luc BRAF V600E melanoma xenograft model.

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.

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.

MEK4 inhibitor 6ff is potent, selective MEK4 inhibitor with IC50 of 66 nM.MEK4 inhibitor 6ff displays excellent selectivity across the entire MEK family, 150-fold more potent against MEK4 than any other MEKkinase, and is at least 385-fold selective against three other MEK kinases.

MEK4 inhibitor 15o is potent, selective, cell permeable MEK4 inhibitor with IC50 of 83 nM.MEK4 inhibitor 10e demonstrated significant reduction of phospho-JNK and antiproliferative properties against pancreatic cancer cell lines, molecular inhibition of MEK4 pathway activates the MEK1/2 pathway.MEK4 inhibitor 10e demonstrated synergistic effects against pancreatic cancer cells with the combination of MEK1/2 inhibitors.

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.

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-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.

KRAS G12C Pipetide (LVVVGACGVGK)

HPK1 inhibitor 1 is a highly potent, selective inhibitor of HPK1/MAP4K1 with biochemical IC50 of 0.0465 nM; displays >100-fold selectivity against 260 kinases in a panel of 265 kinases; HPK1 inhibitor 1 decreased SLP-76 phosphorylation in a human pSLP-76 ELISA at an IC50 lower than 0.02 uM; HPK1 inhibitor 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells; HPK1 inhibitor 1 demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production when combination with pembrolizumab in human PBMCs

GDC-0134 (GDC0134) is a potent, selective, orally available, brain-penetrant inhibitor of dual leucine zipper kinase (DLK, MAP3K12).GDC‐0134 blocks DLK activity in cellular assays and in animal models of neuronal injury.Dual leucine zipper kinase (DLK), which regulates the c‐Jun N‐terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS).

BT2 is a thermostable small-molecule inhibitor of vascular permeability and angiogenesis, interacts with MEK1 and inhibits ERK phosphorylation, FosB/ΔFosB, and VCAM-1 expression.BT2 blocks endothelial FosB/ΔFosB expression, proliferation, migration and wound repair after in vitro injury and network formation.BT2 also inhibited a range of other regulatory genes involved in cell proliferation, migration, angiogenesis, and inflammation including intercellular adhesion molecule-1 (ICAM-1), CXCL2, KLF5, Egr-1, and Fos.BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR.

BSJ-04-122 is a potent, selective, covalent dual MKK4/7 inhibitor with IC50 of 4/181 nM, displays excellent kinome selectivity; BSJ-04-122 covalently targets a conserved cysteine (Cys247 for MKK4, and Cys261 for MKK7) located before the DFG motif. SJ-04-122 exhibits potent cellular target engagement and induces robust target-specific downstream effects. In breast cancer cell lines, BSJ-04-122 potently inhibited JNK phosphorylation, BSJ-04-122 significantly decreased levels of T183/Y185 pJNK at 5 uM, resulting in complete inhibition at 10 uM in MDA-MB-231 cells. The combination of the dual MKK4/7 inhibitor BSJ-04-122 with a selective, covalent JNK inhibitor (JNK-IN-8) demonstrated an enhanced antiproliferative activity against triple-negative breast cancer cells.

A-745 (A745) is a selective and potent HPK1 chemical probe (inhibitor) of HPK1.A-745 demonstrates an excellent cellular selectivity binding profile within pharmacologically relevant concentrations in unbiased cellular kinase-binding assays.A-745 exhibited in vitro immune cell activation phenotype reminiscent of Hpk1-deficient and Hpk1-kinase-dead T cells, including augmented proliferation and cytokine production.A-745 is a selective and potent small molecule HPK1 inhibitors with the pharmacological properties for immunotherapy.

(R)-STU104 is a potent, first-in-class TAK1-MKK3 porotein-protein interaction (PPI) inhibitor with SPR Kd of 71 nM for binding MKK3, disrupting the TAK1 phosphorylating MKK3.(R)-STU104 exhibited the potent inhibitory activity on TNF-α production on RAW264.7 cells with IC50 of 0.58 uM, suppressed the TAK1/MKK3/p38/MnK1/MK2/elF4E signal pathways.(R)-STU104 demonstrated remarkable dose-effect relationships on both acute and chronic mouse ulcerative colitis (UC) models.(R)-STU104 showed better anti-UC efficacy in vivo at 10 mg/kg/d than mesalazine at the dose of 50 mg/kg/d.

DS12881479 (DS 12881479) is a novel potent, selective inhibitor of MAPK-interacting kinase 1 (Mnk1) with IC50 of 21 nM, stabilizes the autoinhibited state of Mnk1.

PD-334581 is a MEK1 inhibitor.

KRAS G12D inhibitor 14 is a potent KRAS G12D inhibitor with a KD of 33 nM for binding to KRAS G12D protein. KRAS G12D inhibitor 14 decreases the active form of KRAS G12D (KRAS G12D-GTP) but not KRAS G13D.

K20 is a potent and selective KRas G12C inhibitor with an IC50 of 1.16 µM. K20 shows anticancer activity in H358 cells (IC50= 0.78 µM). K20 decreases the levels of phosphorylated Erk and leads to cancer cell apoptosis. K20 suppresses NCI-H358 tumor growth with a TGI of 41% without causing obvious toxicity.

KRAS inhibitor-11 (compound 12) is a KRAS inhibitor.

KRAS G12C inhibitor 29 is a KRAS G12C inhibitor extracted from patent WO2021252339A1, compound 3. KRAS G12C inhibitor 29 can be used for the research of cancer.

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).

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).

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).

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 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.

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.

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.