Table 2.

Direct RAS Inhibitors

Name	Potency	Type	Binding Site	Mechanism of Action	Model Tested	Clinical Trials	Selected 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	(Gurpinar, et al., 2014; Herrmann, et al., 1998; Thompson, et al., 1995; Thompson, et al., 1997)
643000 and 117028		Small molecule	P3 pocket?	↓ RAS-GTP	Cell culture		(Grant, et al., 2011)
DCAI	EC50 = 15.8μM	Small molecule	P1 pocket	↓ SOS interaction	Cell culture		(Maurer, et al., 2012)
Cmpd 12	KD = 190μM	Small molecule	P1 pocket	↓ Nucleotide exchange	In vitro		(Sun, et al., 2012)
Kobe0065 and Kobe 2602	IC50 = 10 – 20μM	Small molecule	P1 pocket - state 1 of SW1	↓ SOS-mediated nucleotide exchange and RAF interaction	Cell culture; Mouse colon carcinoma model		(Prakash, et al., 2015a; Shima, et al., 2013)
BI-2852	EC50 = 5.8 – 6.7μM	Small molecule	Pocket between SW1/SW2	↓ GEF, GAP, and effector interactions	Cell culture		(Kessler, et al., 2019)
Cmpd 11	IC50 = 5μM	Small molecule	P1 pocket	↓ RAF interaction	Cell culture		(McCarthy, et al., 2019)
Cmpd2	EC50 = 2.7μM	Small molecule	Membrane/P1 pocket	↓ Effector engagement	Cell culture		(Fang, et al., 2018; Jansen, et al., 2017)
SCH-53239 SCH-53870 SCH-54292	IC50 ≈ 10 – 20μM	Small molecule	Pocket adjacent SW2	↓ Nucleotide exchange	Cell culture		(Peri, et al., 2005; Taveras, et al., 1997)
Cmpd4	> 100μM needed for RAS inhibition	Small molecule	SOS	↑ Nucleotide exchange → negative feedback	Cell culture		(Burns, et al., 2014; Howes, et al., 2018)
cmpd17 cmpd19	> 50μM needed for RAS inhibition	Small molecule	SOS	↑ Nucleotide exchange → negative feedback	In vitro		(Abbott, et al., 2018)
BAY-293	IC50 ≈ 1 – 3μM	Small molecule	SOS	↓ SOS interaction	Cell culture		(Hillig, et al., 2019)
HBS3	Kd = 28 – 158μM	Peptide	SOS1 interaction site	↓ SOS interaction and nucleotide exchange	Cell culture		(Patgiri, et al., 2011)
SAH-SOS1A	IC50 = 5 – 15μM	Peptide	SOS1 interaction site	↓ SOS interaction and nucleotide exchange	Cell culture		(Leshchiner, et al., 2015)
RASGRF1-TAT	Activity observed at 500nM	Peptide	RASGRF1 interaction site	↓ Nucleotide exchange	Cell culture		(Sacco, et al., 2012)
MCP1 and Derivatives	IC50 = 17.9μM	Small molecule	Unknown	↓ RAF interaction	Cell culture; Mouse tumor models		(Gonzalez-Perez, et al., 2010; Skobeleva, et al., 2007)
3144	IC50= 3.8μM	Small molecule	SW1/SW2	↓ Effector interaction	Cell culture; Mouse breast and pancreatic cancer models		(Welsch, et al., 2017)
cyclorasin 9A5	IC50 = 0.12μM	Cyclic peptide	RAS-GTP SW1 loop	↓ RAF interaction	Cell culture		(Upadhyaya, et al., 2015)
Cmpd 12	EC50 = 0.32μM	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		(Ostrem, et al., 2013)
ARS-853	IC50 ≈ 2μM	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		(Patricelli, et al., 2016)
ARS-1620	IC50 = 120nM	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		(Janes, et al., 2018)
MRTX849	IC50 ≅ 10nM	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; Phase I/II clinical trial for patients with advanced solid tumors with KRAS G12C mutation	NCT03785249; Positive results in lung and colon adenocarcinoma patients	(Hallin, et al., 2020)
AMG 510	IC50 = 4 – 32nM	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: Phase I/II clinical trial for patients with advanced solid tumors with KRAS G12C mutation	NCT03600883; Positive results in lung cancer patients	(Canon, et al., 2019)
2C07	βME50 = 1.10 – 2.53mM	Small molecule	SII-G	Stabilizes GDP state; ↓ RAS/SOS interaction and nucleotide exchange and PI3K interaction	In vitro		(Gentile, et al., 2017)
Y13–259		Monoclonal antibody	HRAS SW2	Sequestration of RAS in intracellular aggregates	Cell culture		(Cardinale, et al., 1998; Furth, et al., 1982; Mulcahy, et al., 1985)
anti-p21ser		Monoclonal antibody	Viral KRAS(G12S) residues 5–16	↓ GTP loading	Cell culture		(Clark, et al., 1985; Feramisco, et al., 1985)
iDab#6	Kd = 26 – 180nM	Intrabody	SW1/SW2 of RAS-GTP	↓ Effector interaction	Cell culture; Mouse fibrosarcoma, colorectal cancer, and lung cancer models		(Quevedo, et al., 2018; Tanaka, et al., 2003; Tanaka and Rabbitts, 2010; Tanaka, et al., 2007)
Abd-7	IC50 = 8 – 10μM	Small molecule	P1 pocket	↓ PI3K, RAF, and RALGDS interaction	Cell culture		(Bery, et al., 2018; Quevedo, et al., 2018)
RT11(-i)	IC50 = 5 – 13μM	Chimeric cell-penetrating antibody	RAS-GTP	↓ PI3K, RAF, and RALGDS interaction	Cell culture; Mouse pancreatic, fibrosarcoma, and colorectal cancer models		(Kang, et al., 2018; Shin, et al., 2017; Shin, et al., 2020)
inRas37	IC50 = 1.5 – 8μM						(Shin, et al., 2020)
R11.1.6	Kd = 4 – 40nM	High affinity scaffold based on sso7d	RAS-GTP SW2	↓ GTP hydrolysis and RAF association	Cell culture		(Kauke, et al., 2017)
K27 and K55	IC50 = 2.4 (K27); 167nM (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		(Guillard, et al., 2017)
K13 and K19	K13: Kd = 30nM K19: Kd = 10nM	DARPins	KRAS(G12V) α3-α4 dimerization interface	↓ RAS dimerization, SOS nucleotide exchange, and RAF, PI3K, and RALGDS interaction	Cell culture		(Bery, et al., 2019)
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		(Khan, et al., 2019; Spencer-Smith, et al., 2017; Spencer-Smith, et al., 2019)