Table 2.

Direct RAS inhibitors.

Name	Potency	Type	Binding site	Mechanism of action	Model tested	Clinical trials	References
Sulindac		Small molecule	Unknown	↓ GEF nucleotide exchange, GAP GTPase, RAF interaction	Cell culture; rat breast cancer model; clinical trials	Nearly 40 clinical trials in various cancers	[102,103]
Cyclorasin 9A5*	IC50 = 0.12 μM	Small molecule	RAS-GTP SW1 loop	↓ RAF interaction	Cell culture		[104,180]
MCP1 and derivatives	IC50 = 17.9 μM	Small molecule	Unknown	↓ RAF interaction	Cell culture; mouse tumor models		[106–109]
DCAI	EC50 = 15.8 μM	Small molecule	P1 pocket	↓ SOS interaction	Cell culture		[110]
Cmpd 11	IC50 = 5 μM	Small molecule	P1 pocket	↓ RAF interaction	Cell culture		[113]
Kobe0065 and Kobe2602	IC50 = 10–20 μM	Small molecule	P1 pocket - state 1 of SW1	↓ SOS-mediated nucleotide exchange and RAF interaction	Cell culture; mouse colon carcinoma model		[114]
HBS3	Kd = 28–158 μM	Small molecule	SOS1 interaction site	↓ SOS interaction and nucleotide exchange	Cell culture		[116]
SAH-SOSIA*	IC50 = 5–15 μM	Small molecule	SOS1 interaction site	↓ SOS interaction and nucleotide exchange	Cell culture		[117]
Cmpd2	EC50 = 2.7 μM	Small molecule	Membrane/P1 pocket	↓ Effector engagement	Cell culture		[118,119]
3144	IC5o = 3.8 μM	Small molecule	SW1/SW2	↓ Effector interaction	Cell culture; mouse breast and pancreatic cancer models		[120]
Cmpd 12	EC50 = 0.32 μM	Small molecule	SII-P/C12 of RAS(G12CJ	Disrupts SW1/2 conformation; traps KRAS in a GDP-bound state; ↓ interaction with effectors and activators	Cell culture		[121]
ARS-1620	IC50 = 120 nM	Small molecule	SII-P/C12 of RAS(G12C)	Disrupts SW1/2 conformation; traps KRAS in a GDP-bound state; ↓ interaction with effectors and activators	Cell culture; mouse pancreatic and lung cancer models		[32]
MRTX849	IC50 ≅ 10 nM	Small molecule	SII-P/C12 of RAS(G12C)	Disrupts SW1/2 conformation; traps KRAS in a GDP-bound state; ↓ interaction with effectors and activators	Cell culture; mouse pancreatic cancer model; phase I/II clinical trial for patients with advanced solid tumors with KRAS G12C mutation currently recruiting		[122,123]
AMG 510		Small molecule	SII-P/C12 of RAS(G12C)	Disrupts SW1/2 conformation; traps KRAS in a GDP-bound state; ↓ interaction with effectors and activators	Phase I/II clinical trial for patients with advanced solid tumors with KRAS G12C mutation currently recruiting
2C07	βME50= 1.10–2.53 mM	Small molecule	SII-G	Stabilizes GDP state; ↓ RAS/SOS interaction and nucleotide exchange and PI3K interaction	None		[181]
BI-2852	EC50 = 5.8–6.7 μM	Small molecule	Pocket between SW1/SW2	↓ GEF, GAP, and effector interactions	Cell culture		[115]
Y13–259		Monoclonal antibody	HRAS SW2	Sequestration of RAS in intracellular aggregates	Cell culture		[124–127]
Anti-p21ser		Monoclonal antibody	Viral KRAS(G12S) residues 5–16	↓ GTP loading	Cell culture		[128,129]
iDab#6	Kd = 26–180 nM	Intrabody	SW1/SW2 of RAS-GTP	↓ Effector interaction	Cell culture; mouse fibrosarcoma, colorectal cancer, and lung cancer models		[139–142]
ABD7	IC50 = 8–10 μM	Small molecule	PI pocket	↓ PI3K, RAF, and RALGDS interaction	Cell culture		[142,143]
RT11(-i)	Kd = 4–17 nM	Chimeric cell-penetrating antibody	RAS-GTP	↓ PI3K, RAF, and RALGDS interaction	Cell culture; mouse fibrosarcoma and colorectal cancer models		[144]
R11.1.6	Kd = 4–40 nM	High affinity scaffold based on sso7d	RAS-GTP SW2	↓ GTP hydrolysis and RAF association	Cell culture		[145]
K27 and K55		Designed ankyrin repeat proteins (DARPins)	K27: RAS-GDP SW1 K55: RAS-GTP SW1/SW2 and prevented RAF interaction	K27: ↓ SOS interaction K55: ↓ RAF interaction	Cell culture		[135]
NS1	Kd= 15 nM (HRAS) Kd = 65 nM (KRAS)	Monobody	α4-α5 dimerization interface	↓ H/KRAS dimerization and signaling	Cell culture; mouse pancreatic, endometrial, and lung cancer models		[33,136,137]
K13 and K19	K13: Kd=30 nM K19: Kd=10 nM	DARPins	KRAS(G12 V) α3-α4 dimerization interface	↓ RAS dimerization, SOS nucleotide exchange, and RAF, PI3K, and RALGDS interaction	Cell culture		[161]