Table 1.

Comparative table of recent KRAS targeting strategies. Molecules that are in bold, are shown in Fig. 4 and Supplementary Figure S2, PDB IDs containing those molecules are shown in bold as well

Binding target/site	Effect	Compound type	PDB ID	Representative example	Reference
SI/II-pocket (α2-helix and β1-β3 sheet) in the PPI surface	Inhibition of GEF, GAP, and effector interaction	Small molecule	6GJ5-6GJ8	S1-BI-2852	Kessler-2019 [56]
	GEF-mediated nucleotide exchange inhibition		4DSO, 4DST, 4DSU	S2-Benzimidazole DCAI	Mauer-2012 [55]
	Inhibition of RAS-SOS binding		4EPR, 4EPY, 4EPX, 4EPW, 4EPT, 4EPV	S3–‘Compound-4’	Sun-2012 [57]
	Inhibition of effector interaction		5OCO, 5OCT, 5OCG, 6FA1, 6FA2, 6FA3, 6FA4	S4-ABD-4 S5-ABD-7	Qevedo-2018 [60]
			6GOD, 6GOE, 6GOF, 6GOG, 6GOM, 6GQT, 6GQW, 6GQX, 6GQY	Ch-3	Cruz-Migoni-2019 [59]
Switch-II pocket (S-IIp)	Inhibition of GTP loading to RAS	Covalent small molecule	5F2E	S6-ARS-853	Patricelli-2016 [34]
			5V9U	ARS-1620	Janes-2018 [42]
			6OIM	S7-AMG-510	Canon-2019 [27]
			6UT0	S8-MRTX849	Fell-2020 [28]
P110 pocket on the allosteric lobe of KRAS	Allosteric inhibition of effector interaction	Small molecule	–	KAL-21404358	Feng-2019 [67]
Allosteric lobe of KRAS	Competitive inhibition of GEF	Antibody-like protein	6H46, 6H47	DARPin K13, DARPin K19	Bery-2019 [68]
Hydrophilic pocket in CDC25 domain of SOS	SOS-mediated nucleotide exchange overactivation, biphasic modulation of ERK pathway, through inducing negative feedback	Small molecule	4NYI, 4NYJ, 4NYM	–	Burns-2014 [81]
			6D5W, 6D5V, 6D5M, 6D5L, 6D5J, 6D5G 6D5H, 6D5E, 6D59, 6D56, 6D55	‘Compound-34,’ ‘Compound-65’	Hodges-2018 [72]
	Inhibition of SOS mediated RAS activation.	Small molecule	6EPL, 6EPM, 6EPN, 6EPO, 6EPP 5OVI	S9 BAY-293	Hillig-2019 [73]
					Evelyn-2014 [74]
	Inhibition of SOS-mediated RAS activation	Small molecule	4URU, 4URV, 4URW, 4URX, 4URX, 4URY, 4URZ, 4US0, 4US1, 4US2	S10, S11	Winter-2015 [75]
RAS-SOS interface	Stabilizing RAS-SOS complex
Covalent bond with C118 of RAS near guanosine binding site	Disrupting nucleotide binging, disruption of effector binding	Covalent small molecule
Nucleotide binding site	Disrupting effector interaction	Covalent guanosine analogue	5KYK	S12 XY-02-075	Xiong-2017 [45]
PPI surface	Binding to PPI in GTP-bound state, obstructing effector interaction	Antibody	–	–	Shin-2017 [64]
		Antibody-like protein	5O2S, 5O2T	DARPin K27, DARPin K55	Guillard-2017 [62]
Switch-II pocket (S-IIp)	Inhibition of RAS-SOS complex	Peptide	5XCO	RT11	Sogabe-2017 [54]
RAS-GAP interface	Promoting RAS-GAP interaction	Small molecule	–	S13	Nyíri-2020 [83]