. 2023 Mar 21;31(7):1904–1919. doi: 10.1016/j.ymthe.2023.03.017

Table 1.

Summary of small molecules targeting KRAS

Selected small molecules targeting mutant KRAS
Compound	Method of delivery	RAS Target	Concentration	In vitro studies	In vivo studies	Clinical trials	Ref(s).
AMG510 (Sotorasib or LUMA-KRAS)	Small molecule, His95 groove binder	KRAS G12C	0.010–0.123 μM in 22 cell lines that had heterozygous or homozygous KRAS^G12C expression	in KRAS^G12C cell lines, NCI-H358 and MIA PaCa-2, AMG 510 almost completely inhibited p-ERK (IC₅₀ ≈ 0.03 μM) after a 2-h treatment	200 mg/kg AMG 510 resulted in inhibition of p-ERK in MIA PaCa-2 T2 and NCI-H358 tumors	Anticancer activity in 129 patients with locally advanced KRAS G12C-mutant solid tumors, Fast Track designation and undergoing a phase III study	²³^,²⁴^,²⁵^,²⁶
MRTX849 (Adagrasib)	Small molecule, covalent KRAS G12C inhibitor	KRAS G12C	inhibited cell growth of KRAS^G12C-mutant cell lines with IC₅₀ values ranging between 0.2 and 1,042 nM in the 3-D format	inhibited pERK; Thr²⁰²/Tyr²⁰⁴ ERK1, pS6; Ser^235/236, and DUSP6, around 4.7 nM IC50s in KRAS^G12C-mutant H358 lung and MIA PaCa-2	Tumor regression in 17 of 26 (65%) KRAS^G12C-positive cell line- and patient-derived xenograft models from multiple tumor types at a maximum tolerable dose between 30 and 100 mg/kg/day	ORR was 43%, the DCR was 80% in 112 KRAS G12C NSCLC patients, received Breakthrough Therapy designation, undergoing phase III study	²⁷^,²⁸^,²⁹^,³⁰
RG6330/GDC-6036	Small molecule, selective KRAS G12C inhibitor	KRAS G12C	IC₅₀ of <0.01 μM	EC₅₀ of 2 nM in K-RAS G12C-alkylation HCC1171 cells	Tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models	Recruiting patients for a phase Ia/Ib dose-escalation and dose-expansion study	³¹^,³²^,³³
D-1553	Small molecule, selective KRAS G12C inhibitor	KRAS G12C	ND	anti-tumor activity across a panel of cancer cell lines including lung, pancreatic and colorectal cancers with KRAS-G12C mutation	Highly potent in vivo in various cell line-derived xenograft tumor models with KRAS-G12C mutation	Undergoing phase I/II open label study	³⁴^,³⁵
BI 1829311	KRAS^G12C selective small molecule inhibitor	KRAS G12C	ND	In a KRAS^G12C NSCLC cell line panel, downregulates DUSP6 and CCND1, and p-ERK	Daily oral dose of 60 mg/kg in a panel of lung and colon, mouse models showed comparable efficacy to AMG 510 and MRTX849	Recruiting patients for phase Ia/Ib, open-label, multicenter dose-escalation, and expansion study	³⁶^,³⁷
JAB-21822	Covalent KRAS G12C inhibitor	KRAS G12C	<10–5000 nM in Ba/F3 cell lines bearing G12C mutation or secondary mutations	Cell growth inhibition in a variety of G12C mutant cancer cell lines	50-100% tumor growth inhibition in CDX (10 mg/kg PO daily) or PDX (100 mg/kg PO daily) mouse models bearing G12C mutations	Undergoing phase I/II study, in the 800 mg daily cohort, ORR = 50% and DCR = 100% with 4 non-confirmed PR	³⁸^,³⁹^,⁴⁰
JDQ443	Small molecule covalent KRAS G12C inhibitor (GDP-bound)	KRAS G12C	0.02 μM in KRAS G12C-mutated NCI-H358 cells,	Currently optimizing compound potency, reduced cell proliferation and cRAF recruitment in NCI-H2122/NCI-H1437 and Ba/F3 KRAS mutants	30–100 mg/kg reduced tumor growth in multiple tumor xenograft and CDX models	Undergoing multiple clinical studies in G12C mutant NSCLC, CRC, and other patients	⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶
MK-1084	KRAS G12C inhibitor	KRAS G12C	ND	ND	ND	Phase I study alone and in combination with pembrolizumab in NSCLC KRAS G12C patients	⁴⁷
K20	inhibitor of KRAS G12C (GTP bound)	KRAS G12C	IC₅₀ of 0.78 μM in H358 cells and 1.55 μM H23 mutant G12C cells	2.5 μM inhibited colony formation, induced apoptosis and reduced p-ERK levels in H23 and H358 cells	Tumor growth inhibition of 41% at 35 mg/kg and reduced p-ERK levels	NA	⁴⁸
ARS-1620	atropisomeric selective KRASG12C inhibitor (GDP-bound)	KRAS G12C	IC₅₀ < 0.3 μM across a panel of cancer cell lines harboring either KRAS p.G12C (H358, MIA-PaCa2, and LU65)	in 3 G12C mutant cell lines, 150 nM reduced cell viability and p-ERK expression, also tested in 2D and 3D systems	Tumor growth inhibition at 200 mg/kg daily in MiaPaCa2 and PDX mutant G12C models	NA	⁴⁹
RM-018	KRAS G12C “tricomplex” inhibitor (GTP bound)	KRAS G12C	ND	attenuated both RAS-MAPK signaling and cell viability in cancer cell lines bearing KRAS^G12Cmutations	Dose-dependent tumor regression in the NCI-H358 KRAS^G12CNSCLC xenograft mouse model	NA	⁵⁰^,⁵¹
SML-8–73-1, SML-10-70-1	small molecule, GTP-competitive inhibitor of K-RAS	KRAS G12C	26.6–100 mM	attenuated Akt and Erk phosphorylation at a concentration of 100 mM, antiproliferative effects in A549, H23, and H358 cells	NA	NA	⁵²^,⁵³
HRS-4642	Small molecule that targets KRAS G12D	KRAS G12D	ND	ND	ND	Phase I study to evaluate the safety, tolerability, and pharmacokinetics in patients with advanced solid tumors with KRAS G12D mutations	⁵⁴^,⁵⁵
BI-2852	KRAS inhibitor for the switch I/II pocket	KRAS G12D	binds to KRAS^G12Dwith a KD of 740 nM	inhibits GTP-KRAS^G12D binding to SOS1, CRAF, and PI3Kα with an IC₅₀ of 490, 770, and 500 nM pERK modulation and antiproliferative effects in NCI-H358	NA	NA	⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹
MRTX1133	noncovalent KRAS G12D inhibitor for the switch II pocket	KRAS G12D	0.2 pM	inhibited ERK phosphorylation in the AGS cell line with an IC50 of 2 nM in a 2D viability assay, the IC50 of MRTX1133 was 6 nM against the same cell line, with 500-fold higher selectivity against MKN1 cells	Antitumor activity with 94% growth inhibition observed at 3 mg/kg twice daily (i.p.) and tumor regressions of −62% and −73% observed at 10 and 30 mg/kg twice daily, in KRASG12D mutant Panc 04.03 cell line	NA	⁶⁰
RMC-6236	RAS-MULTI(ON) inhibitor	RAS mutants	ND	ND	ND	Phase I clinical evaluation for patients with KRAS G12A, G12D, G12R, G12S, or G12V mutations	⁵⁵^,⁶¹^,⁶²
KRA-533	small molecule KRAS agonist, binds the GTP/GDP-binding pocket of KRAS	KRAS mutants	10 μM	10 μM induced cell death in mutant KRAS cell lines A549, H157, Calu-1, and H292	7.5, mg/kg/day of KRA-533 i.p. for 28 days suppressed tumor growth in a dose-dependent manner in A549 xenografts	NA	⁶³
THZ835	small molecule, binds GDP and GTP-bound KRAS, disrupts the KRAS–CRAF interaction	KRAS G12D	low μM range	reduced pERK and pAKT levels, increased p21 and p27 levels and reduced CDK2/4/6 and cyclin D1 expression cells went through G1 cell-cycle arrest and apoptosis	Mouse xenograft models of pancreatic cancer exhibited reduced tumor growth but mice experienced weight loss, suggesting the potential of off-target effects	NA	⁶⁴
KAL-21404358	small molecule allosteric ligand against P110 site	KRAS G12D	K_D of 100 μM	impaired the interaction of K-RAS^G12Dwith B-Raf and disrupted the RAF-MEK-ERK and PI3K-AKT signaling pathways	NA	NA	⁶⁵
12VC1	monobody, noncovalent inhibitor	KRAS G12V and G12C	expressed intracellularly alone or fused to VHL	inhibits ERK activation and the proliferation of RAS-driven cancer cell lines	H23 cells expressing VHL-12VC1 were significantly smaller than control tumors	NA	⁶⁶
NS1 (aHRAS)	monobody, inhibits RAS-mediated signaling through targeting the α4–α5 surface	KRAS and HRAS	expressed intracellularly alone or fused to VHL	inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation	NA	NA	³^,⁶⁷
Compound 3144	multivalent small-molecule, pan-RAS inhibitor	KRAS HRAS NRAS	K_d of 4.7/17/6.6/3.7 μM for KRAS G12D/KRAS wt/HRAS/NRAS, respectively	lethality in cells partially dependent on expression of RAS proteins	Displays anti-tumor activity in breast and pancreatic xenografts	NA	⁶⁸^,⁶⁹
DCAI (dichloro-2-methyl-3-aminoethyl-indole)	competitive inhibitor that blocks the RAS-SOS^cat interaction	KRAS, KRAS mutant	15.8 ± 0.4 μM	blocks the recruitment of the cRaf RBD-CRD domain to the cytoplasmic membrane, effect on cell viability ND	NA	NA	⁷⁰

Two G12C inhibitors, JNJ-74699157 and LY3499446, are not included as these compounds failed clinical trials.⁷¹^,⁷²

Revolution Medicines is also developing RMC-6291, a KRAS^G12C inhibitor, RMC-9805, a KRAS^G12D inhibitor and RMC-8839, a KRAS^G13Cinhibitor.

Jacobio Pharma is developing small molecule inhibitors: JAB-23400 (KRAS (multi)) and JAB-22000 (KRAS G12D).

Bridge Bio is performing preclinical studies for multiple compounds including the KRAS inhibitor BBP-454 and PI3Ka:RAS breakers.

CRC, colorectal cancer; DCR, disease control rate; ND, not disclosed; NA, information is not available; ORR, objective response rate; PI3K, phosphatidylinositol 3-kinase.