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 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.

Automated summary

Balanced pan-class I phosphoinositide 3-kinase inhibition is a promising approach for cancer treatment, offering the potential to treat various tumor types and enhance efficacy with a single inhibitor. This study identified a best-in-class phosphoinositide 3-kinase inhibitor, 40 (NVP-CLR457), by optimizing its properties, including eliminating off-target activity and balancing the inhibition profile.