Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer

Abstract

T he phosphoinositide-3-kinase (PI3K) family of lipid kinases is involved in a diverse set of cellular functions, including cell growth, proliferation, motility, differentiation, glucose transport, survival, intracellular trafficking, and membrane ruffling. 1 PI3K's can be categorized into class I, II, or III, depending on their subunit structure, regulation, and substrate selectivity. 2 Class IA PI3K's are activated by receptor tyrosine kinases and consist of a regulatory subunit (p85) and a catalytic subunit (p110). There are three catalytic isoforms: p110R, β, and δ. A single class IB PI3K, activated by GPCRs, consists of only one member: a p110γ catalytic subunit and a p101 regulatory subunit. The primary in vivo substrate of the class I PI3K's is phosphatidylinositol (4,5) diphosphate (PtdIns(4,5)P2), which upon phosphorylation at the 3-position of the inositol ring to form phosphatidylinositol triphosphate (3,4,5)P3 (PIP3) serves as a second messenger by activating a series of downstream effectors that mediate the cellular functions mentioned above. The PI3K isoforms have different distributions and share similar cellular functions, which are context dependent. In particular, p110R pathway deregulation has been demonstrated in ovarian, breast, colon, and brain cancers. 3,4 Inhibitors of PI3KR represent an intriguing therapeutic modality for these indications, and as such, there is much interest in generating suitable molecules to test this hypothesis in the clinic. 5À10 We have previously reported on a series of 6-hydroxyphenyl-2-morpholino pyrimidines, 11 as potent pan class I PI3K inhibitors that exhibit high selectivity toward protein kinases (serine/threonine and tyrosine kinases). We have further reported on non-phenol containing heterocyclic, morpholino pyrimidines 12 such as compound 1 which demonstrate in vivo PI3K pathway modulation and modest tumor growth inhibition. Described herein are our efforts to identify potent morpholino pyrimidinyl inhibitors of class I PI3Ks that exhibit potency and pharmacokinetic properties which allow for maximal pathway modulation in vivo and have druglike properties suitable for clinical development. These efforts culminated in the identification of 15, NVP-BKM120.Aminopyrimidine 1 and analogues such as 3 (Figure 1) exhibit low or sub-nanomolar biochemical potency and sub-micromolar cellular potency against PI3KR. Even with high rodent CL values, such analogues can demonstrate PI3K pathway modulation in mouse xenograft models. 12 During our exploration of the C 6 position, it was noted that C 6 aminopyridine analogue 4, while being less potent than 3 against PI3KR (>10Â potency loss), exhibited a markedly reduced (>9Â) rat CL value, increased %F, and increased oral AUC. Thus, superior pharmacokinetic properties were achievable within this scaffold and the challenge remaining was to retain this kind of pharmacokinetic profile while optimizing all the other attributes (potency, solubility, permeability, safety) necessary for advancement. To address this challenge, ...

Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

“…This effort led to the discovery of NVP-BKM120, identified from the pan-PI3K inhibitor lead series 2-morpholino-4-amino-6-pyrimidinyl pyrimidines (MAPP) through a combination of structure-based drug design and optimization of in vivo properties (37). NVP-BKM120 inhibits PI3K in an ATP competitive manner, but this is the result of a mixed effect on K m and V max .…”

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…The biochemical activity of NVP-BKM120 was observed for the inhibition of VPS34, mTOR, DNAPK, and PI4K. The drug exerts antitumor activity against two models of PI3K/Akt pathway driven cancers: the A2780 ovarian carcinoma model and the U87MG glioma model, which carry a PTEN deletion [80] . It has also been observed that the inhibition of glioma cells by NVP-BKM120 depends upon the mutational status of p53.…”

Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

“…41,42 Buparlisib has potent, pan-class I PI3K inhibitory PROPERTIES against p110-α, -β, -δ, and -γ enzymes at IC 50 of 52, 166, 116, and 262 nM, respectively. 43 Other panclass I PI3K inhibitors in clinical development include XL147 (IC 50 of 39, 36, 23, and 383 nM against p110-α, -β, -δ, and -γ, respectively), GDC-0941 (pictilisib; IC 50 of 3 nM against p110-α and -δ enzymes), BAY80-6946 (copanlisib; IC 50 of 0.469 nM against p110-α and 3.72 nM against p110-β), PX-866 (sonolisib; IC 50 of 0.1-88 nM), and CH5132799 (IC 50 of 14 nM against p110-α). [44][45][46][47][48][49] …”