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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146260
    Pan-class I PI3K Inhibitor