Discovery of PF-04691502 (PI3K/mTOR dual inhibitor)


Rapamycin and it’s analogues (or rapalogues e.g. CCI-779) modulate the phosphatidylinositol 3-kinase (PI3K) signalling cascade by binding to an allosteric site on the mTORC1 complex (Mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, forms two functional complexes, mTORC1 and mTORC2).  mTOR plays a major role in regulating cell growth and proliferation and it’s aberrant function is implicated in a number of cancers.  However, whilst rapalogues do demonstrate clinical benefits in cancer patients, it is now thought that inhibiting both mTORC1 and mTORC2 simultaneously will result in improved efficacy. Consequently, numerous groups have pursued mTOR active site inhibitors (common to both active complexes) and, in addition, the highly homologous active site of the Class 1 PI3Ks, which activate mTOR, has made dual PI3K/mTOR inhibitors still more attractive as potential cancer therapeutics (see a recent review for more information and details of compounds currently undergoing clinical evaluation).

A recent paper from Pfizer describes some of their work in this area.  Following high-throughput screening, an early lead (2) with good pI3Kα potency and high ligand efficiency (0.48) was identified.  Compound 2 had moderate activity at mTOR but otherwise was selective across a panel of other protein kinases.  An x-ray co-crystal structure (PDB3ML8) of 2 bound into the active site of PI3Kγ  was used to guide subsequent optimisation efforts (key binding motifs are highlighted below).  Compound 2 had poor pharmacokinetics (high in vitro clearance) and the group’s design strategy focused on replacing any metabolic hot spots whilst maintaining drug-like physical properties and, at the same time, improving the mTOR activity.

The benzyl alcohol was the first group identified as conferring a metabolic liability and N-dealkylation of the N-methylaminopyrimidine was also anticipated to be a likely metabolic pathway.  Isosteric replacements for the benzyl alcohol were introduced and the desmethyl aminopyrimidine analogues were prepared whilst ensuring that logP and MW were not increased significantly.  2-Methoxypyridines were identified as the preferred benzyl alcohol replacements and, in combination with the desmethyl amino modification, were found to lower clearance and improve mTOR potency (the N-Me substituent was postulated to make an unfavourable interaction with the mTOR protein).  The cyclopentyl group in 2 was then modified to optimise potency and improve solubility through the addition of polar substituents.  Hydroxyethyl-substituted cyclohexanol in this position gave the optimal balance of properties and led to the identification of their clinical candidate, PF-04691502 (Ki=0.57 and 16 nM at PI3Kα and mTOR respectively), which was subsequently advanced into a phase I clinical trial.  The progression from 2 to PF-04691502 nicely illustrates the use of structure-based design to optimise multiple physicochemical properties and the authors illustrate this succinctly (see below) using a plot of the mPI3Kα potency vs cLogP overlaid with contours of equivalent lipophilic efficiency (LipE).  In moving from compound 2 to the eventual candidate 1 (PF-04691502) the LipE was increased from under 6 to about 8.  The x-ray co-crystal structure (PDB3ML9) of PF-04691502 revealed a number of interesting features (see above), including a water-mediated H-bond and an internal H-bond.

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