Identification of GNE-293, a potent and selective PI3Kδ inhibitor: navigating in vitro genotoxicity while improving potency and selectivity

  • Bioorg Med Chem Lett. 2013 Sep 1;23(17):4953-9. doi: 10.1016/j.bmcl.2013.06.052.
Brian S Safina  1 ,  Zachary K Sweeney ,  Jun Li ,  Bryan K Chan ,  Angelina Bisconte ,  Diane Carrera ,  Georgette Castanedo ,  Michael Flagella ,  Robert Heald ,  Cristina Lewis ,  Jeremy M Murray ,  Jim Nonomiya ,  Jodie Pang ,  Steve Price ,  Karin Reif ,  Laurent Salphati ,  Eileen M Seward ,  Binqing Wei ,  Daniel P Sutherlin
Affiliations
  • 1. Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, United States. [email protected]
PMID: 23867164 DOI: 10.1016/j.bmcl.2013.06.052
Abstract

In an effort to identify potent and isoform selective inhibitors of PI3Kδ, GNE-293 (34) was identified. Inhibitor 2 was found to induce micronuclei formation in both the MNT and HCA in vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications of the 2-benzimidazole substituent and the methylene moiety to disrupt planarity. A variety of heteroatom linkers were explored to examine their effect on potency and isoform selectivity by restricting torsional angles to favor ligand interactions with PI3Kδ's Trp760. These modifications also resulted in an improved in vivo pharmacokinetic profile.

Keywords
B-cell inhibition; Genotox; HCA; MNT; PI3K isoform selectivity; PI3K δ.
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