BI-3406

BI-3406
Clinical data
Drug class	SOS1 inhibitor
Identifiers
	IUPAC name N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine;
CAS Number	2230836-55-0;
PubChem CID	138911318;
ChemSpider	78317621;
UNII	P49LSH4TMF;
ChEMBL	ChEMBL4519023;
PDB ligand	L7H (PDBe, RCSB PDB);
Chemical and physical data
Formula	C23H25F3N4O3
Molar mass	462.473 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=NC2=CC(=C(C=C2C(=N1)N[C@H](C)C3=CC(=CC(=C3)N)C(F)(F)F)O[C@H]4CCOC4)OC;
	InChI InChI=1S/C23H25F3N4O3/c1-12(14-6-15(23(24,25)26)8-16(27)7-14)28-22-18-9-21(33-17-4-5-32-11-17)20(31-3)10-19(18)29-13(2)30-22/h6-10,12,17H,4-5,11,27H2,1-3H3,(H,28,29,30)/t12-,17+/m1/s1; Key:XVFDNRYZXDHTHT-PXAZEXFGSA-N;

BI-3406 is a drug that acts as an inhibitor of the guanine nucleotide exchange factor protein SOS1, and prevents it from binding to its target protein KRAS. It has potential applications in the treatment of cancer, and has been widely used in cancer research either in combination with other drugs or as a lead compound for the development of related compounds.^[1]^[2]^[3]^[4]^[5]^[6]^[7]

References

^ Ramharter J, Kessler D, Ettmayer P, Hofmann MH, Gerstberger T, Gmachl M, et al. (May 2021). "One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS". Journal of Medicinal Chemistry. 64 (10): 6569–6580. doi:10.1021/acs.jmedchem.0c01949. PMID 33719426.
^ Kessler D, Gerlach D, Kraut N, McConnell DB (June 2021). "Targeting Son of Sevenless 1: The pacemaker of KRAS". Current Opinion in Chemical Biology. 62: 109–118. doi:10.1016/j.cbpa.2021.02.014. PMID 33848766.
^ Ma Y, Schulz B, Trakooljul N, Al Ammar M, Sekora A, Sender S, et al. (September 2022). "Inhibition of KRAS, MEK and PI3K Demonstrate Synergistic Anti-Tumor Effects in Pancreatic Ductal Adenocarcinoma Cell Lines". Cancers. 14 (18): 4467. doi:10.3390/cancers14184467. PMC 9497071. PMID 36139627.
^ Daley BR, Vieira HM, Rao C, Hughes JM, Beckley ZM, Huisman DH, et al. (November 2023). "SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status". Proceedings of the National Academy of Sciences of the United States of America. 120 (47) e2313137120. Bibcode:2023PNAS..12013137D. doi:10.1073/pnas.2313137120. PMC 10666034. PMID 37972068.
^ Hamilton G, Stickler S, Rath B (2023). "Targeting of SOS1: from SOS1 Activators to Proteolysis Targeting Chimeras". Current Pharmaceutical Design. 29 (22): 1741–1746. doi:10.2174/1381612829666230418114520. PMID 37073657.
^ Thatikonda V, Lyu H, Jurado S, Kostyrko K, Bristow CA, Albrecht C, et al. (September 2024). "Co-targeting SOS1 enhances the antitumor effects of KRAS^G12C inhibitors by addressing intrinsic and acquired resistance". Nature Cancer. 5 (9): 1352–1370. doi:10.1038/s43018-024-00800-6. PMC 11424490. PMID 39103541.
^ Baltanás FC, Kramer-Drauberg M, García-Navas R, Patrucco E, Petrini E, Arnhof H, et al. (March 2025). "SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRAS^G12D inhibitor in KRAS LUAD". Proceedings of the National Academy of Sciences of the United States of America. 122 (11) e2422943122. Bibcode:2025PNAS..12222943B. doi:10.1073/pnas.2422943122. PMC 11929440. PMID 40073053.

[1] Ramharter J, Kessler D, Ettmayer P, Hofmann MH, Gerstberger T, Gmachl M, et al. (May 2021). "One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS". Journal of Medicinal Chemistry. 64 (10): 6569–6580. doi:10.1021/acs.jmedchem.0c01949. PMID 33719426.

[2] Kessler D, Gerlach D, Kraut N, McConnell DB (June 2021). "Targeting Son of Sevenless 1: The pacemaker of KRAS". Current Opinion in Chemical Biology. 62: 109–118. doi:10.1016/j.cbpa.2021.02.014. PMID 33848766.

[3] Ma Y, Schulz B, Trakooljul N, Al Ammar M, Sekora A, Sender S, et al. (September 2022). "Inhibition of KRAS, MEK and PI3K Demonstrate Synergistic Anti-Tumor Effects in Pancreatic Ductal Adenocarcinoma Cell Lines". Cancers. 14 (18): 4467. doi:10.3390/cancers14184467. PMC 9497071. PMID 36139627.

[4] Daley BR, Vieira HM, Rao C, Hughes JM, Beckley ZM, Huisman DH, et al. (November 2023). "SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status". Proceedings of the National Academy of Sciences of the United States of America. 120 (47) e2313137120. Bibcode:2023PNAS..12013137D. doi:10.1073/pnas.2313137120. PMC 10666034. PMID 37972068.

[5] Hamilton G, Stickler S, Rath B (2023). "Targeting of SOS1: from SOS1 Activators to Proteolysis Targeting Chimeras". Current Pharmaceutical Design. 29 (22): 1741–1746. doi:10.2174/1381612829666230418114520. PMID 37073657.

[6] Thatikonda V, Lyu H, Jurado S, Kostyrko K, Bristow CA, Albrecht C, et al. (September 2024). "Co-targeting SOS1 enhances the antitumor effects of KRAS^G12C inhibitors by addressing intrinsic and acquired resistance". Nature Cancer. 5 (9): 1352–1370. doi:10.1038/s43018-024-00800-6. PMC 11424490. PMID 39103541.

[7] Baltanás FC, Kramer-Drauberg M, García-Navas R, Patrucco E, Petrini E, Arnhof H, et al. (March 2025). "SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRAS^G12D inhibitor in KRAS LUAD". Proceedings of the National Academy of Sciences of the United States of America. 122 (11) e2422943122. Bibcode:2025PNAS..12222943B. doi:10.1073/pnas.2422943122. PMC 11929440. PMID 40073053.

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See also

References