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

Basic Information

ID: ALA5137017

Journal: J Med Chem

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

Authors: Fairhurst RA, Furet P, Imbach-Weese P, Stauffer F, Rueeger H, McCarthy C, Ripoche S, Oswald S, Arnaud B, Jary A, Maira M, Schnell C, Guthy DA, Wartmann M, Kiffe M, Desrayaud S, Blasco F, Widmer T, Seiler F, Gutmann S, Knapp M, Caravatti G.

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.

CiteXplore: 35500094

DOI: 10.1021/acs.jmedchem.2c00267

Patent ID: