Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design

Abstract

PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structurebased drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.

PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity

“…No significant inhibitory activity was observed in more than 80 protein kinases at concentration up to 10 mmol/L including the class III PI3K family member hVps34 (12% inhibition at 1 mmol/L), PI3K downstream kinases AKT, PDK1, p70S6K (IC 50 > 10 mmol/L), and MAPK family members such as MEK, ERK, p38, and JNK (IC 50 > 10 mmol/L; ref. 17). Thus, PF-04691502 was shown to be a selective inhibitor of class I PI3K and mTOR.…”

“…The biochemical protein kinase assays for class I PI3K and mTOR were assessed as previously described (17).…”

“…A number of PI3K-selective and PI3K/mTOR-dual inhibitors have entered clinical trials (3,11). PF-04691502, a potent ATP competitive PI3K/mTOR dual inhibitor, was discovered through high-throughput screening and structure-based drug design (17). Here, we present its biochemical and cellular profiles, antitumor efficacy, and pharmacokinetic/pharmacodynamic correlations.…”

An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

“…To examine whether established Pik3ca H1047R Pten del/del tumors remained dependant on PI3K pathway activity for tumor maintenance, we utilized an ATP-competitive PI3K/mTOR inhibitor, PF04691502, currently in phase I clinical trials (26,27). Treatment of Pik3ca H1047R Pten del/del mice commenced 10 weeks following AdCre exposure ( Figure 3M), and tumor progression was monitored by ultrasound (Supplemental Figure 8).…”

Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

“…Based on preclinical studies, phase I clinical trials are underway to assess safety and tolerability of these drugs in cancer patients with solid tumors [56,57].…”