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.