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
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cited_by cdi_FETCH-LOGICAL-a278t-5122a141e5c0a76dacc3ba1feff7b70de8f8d49d5f9c8c7fbfe5f7e1866946433
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container_issue 12
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container_title Journal of medicinal chemistry
container_volume 65
creator 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
description 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.
doi_str_mv 10.1021/acs.jmedchem.2c00267
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title Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor
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