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

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...

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Published in:Journal of medicinal chemistry 2022-06, Vol.65 (12), p.8345-8379
Main Authors: Fairhurst, Robin A., Furet, Pascal, Imbach-Weese, Patricia, Stauffer, Frédéric, Rueeger, Heinrich, McCarthy, Clive, Ripoche, Sebastien, Oswald, Susanne, Arnaud, Bertrand, Jary, Aline, Maira, Michel, Schnell, Christian, Guthy, Daniel A., Wartmann, Markus, Kiffe, Michael, Desrayaud, Sandrine, Blasco, Francesca, Widmer, Toni, Seiler, Frank, Gutmann, Sascha, Knapp, Mark, Caravatti, Giorgio
Format: Article
Language:English
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c00267