molecules of the month

compound 1

oral RET kinase inhibitor

effective in tumor xenograft model

from scaffold hopping & optimization

ACS Medicinal Chemistry Letters

Novartis Genomics Institute

Chemical structure of molecule compound 1 Novartis RET inhibitor
1 min read

14.  The Novartis RET inhibitor, compound 1, demonstrated robust oral in vivo efficacy in RET-driven tumor xenografts at low doses (10 mpk QD). RET inhibitors (selpercatinib and pralsetinib) have recently been approved in RET+ cancers based on significant efficacy in selected patients. Compound 1 was advanced through preclinical studies including rat toxicology but does not appear to have progressed further. It possesses a significantly different structure from the approved RET inhibitors and has interesting bicyclooctane and aniline motifs. The aniline appears to make two critical hydrogen-bonding interactions deep into the active site [based on an analog’s X-ray crystal structure (PDB = 7RUN)] and would be non-trivial to replace.

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