Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor

  • J Med Chem. 2022 Jun 23;65(12):8345-8379. doi: 10.1021/acs.jmedchem.2c00267.
Robin A Fairhurst  1 ,  Pascal Furet  1 ,  Patricia Imbach-Weese  1 ,  Frédéric Stauffer  1 ,  Heinrich Rueeger  1 ,  Clive McCarthy  1 ,  Sebastien Ripoche  1 ,  Susanne Oswald  1 ,  Bertrand Arnaud  1 ,  Aline Jary  1 ,  Michel Maira  1 ,  Christian Schnell  1 ,  Daniel A Guthy  1 ,  Markus Wartmann  1 ,  Michael Kiffe  1 ,  Sandrine Desrayaud  1 ,  Francesca Blasco  1 ,  Toni Widmer  1 ,  Frank Seiler  1 ,  Sascha Gutmann  1 ,  Mark Knapp  2 ,  Giorgio Caravatti  1
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland.
  • 2. Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
PMID: 35500094 DOI: 10.1021/acs.jmedchem.2c00267
Abstract

Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to Cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K Inhibitor 40 (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of 40 in a clinical study is discussed.

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