SOS1-IN-1-15

Close analog with improved potency and invivo properties is described see compound 13c, in ref: J. Med. Chem. 2022, 65, 19, 13158-13171

The tetra-cyclic quinazoline derivative is a potent and selective inhibitor of the SOS1–KRAS interaction, which has shows a more potent tumour inhibition than the SOS1–KRAS inhibitor BI-3406 currently in clinical trials, in the Mia-paca-2 tumor xenograft model. This compound also posses a 2-fold higher drug exposure and 2.5-fold longer half-life than BI-3406 in mouse plasma. However, pre-clinic investigations shows that SOS1-IN-1-15 still presents a level of cardiotoxicity that has warranted further optimisation. In fact, the same team of researchers has developed an optimised compound (PMID: 36173339) which is a very close derivative of SOS1-IN-1-15. To improve the binding affinity of the inhibitor based on the cocrystal X-ray structure of BI-3406 bound to SOS1, the researchers have enlarged the third ring moiety of the tetracyclic quinazoline scaffold by adding one carbon, so going from a six membered ring to a seven membered ring. This derivative has been evaluated in clinical trials. It presents a much lower risk of sudden cardiac death than both SOS1-IN-1-15 and BI-3406, and possess improved bioavailability, in vivo anticancer efficacy, and ADMET-properties. Furthermore, for the optimised compound more in vivo data are available (including PK studies in dogs) than the “predecessor” SOS1-IN-1-15.