Following in silico screening of the ZINC compound database, which comprises 2.5 million compounds, a total of 89 new chemotypes were identified, biochemical screening subsequently led to the discovery of seven new compounds displaying activity between 1 and 100?M of which 38 was the most active, displaying pan PI3K inhibition with an IC50 of 0.9?M, 3?M, 0.9?M and 4?M against p110?? ?? ???and ???respectively. Gilbert and colleagues at Wyeth have reported the discovery of two structurally related series based on purinepyrimidines and pyrazolopyrimidines, LY2228820 
. Interestingly, subtle structural changes were seen to lead to dramatic alterations in subtype selectivity: compound 39 had an IC50 of 58nM against p110????and displayed good selectivity over p110??and mTOR, whereas 40 showed more dual p110??mTOR activity, though with high selectivity over p110?? Venkatesan and co workers at Wyeth have outlined the development of imidazolopyrimidine derivatives exhibiting selective inhibition of both the class I isoforms and mTOR.
An example of such a compound is 41, which had an IC50 of 16nM and 265nM against p110???and p110???respectively, but was inactive against mTOR. In a separate report, the same team also described the design, Asiatic acid synthesis, and characterization of the highly potent bismorpholino 1,3,5 triazine derivative 42, a potent dual class I PI3K/mTOR inhibitor. This compound was seen to inhibit cell survival and proliferation, and to increase apoptosis in vitro and in vivo. PKI 587 also exerted potent anti tumour efficacy in preclinical subcutaneous and orthotopic tumour xenograft models, and has now entered phase I clinical trials. A further report from Venkatesan et al. outlined the development of a related series of 1,3,5 triazine derivatives, targeted with the aim of improving the physicochemical properties of PKI 587.
Incorporation of a 3 oxa 8 azabicyclooctane group in place of a morpholine resulted in the design of PKI 179, 43, which displayed potent in vitro activity. PKI 179 also has high oral bioavailability, and anti tumour efficacy in the MDA 361 human breast tumour xenograft model. The compound was subsequently advanced into a phase I solid tumour study, though this trial has now been terminated. In a subsequent disclosure, it was revealed that, in in vitro studies, a major metabolite of PKI 179, 44, was generated following incubation in human liver microsomes, Chen and co workers confirmed that this metabolite displayed comparable in vitro potency to that of PKI 179. Dehnhardt et al. at Wyeth have described the discovery of a series of triazolopyrimidines, which led to the development of PKI 402, 45, a dual p110??mTOR inhibitor.
PKI 402 displayed high anti proliferative activity in tumour cell lines, induced apoptosis in vitro, and conferred potent anti tumour efficacy in several tumour xenograft models. In a further report, Zhang and co workers at Wyeth outlined the discovery of a novel class of 5 ureidobenzofuran 3 one indoles also displaying potent p110??mTOR activity, exemplified by 46, which displayed very high biochemical activity with concomitant in vitro tumour cell growth inhibition. Compound 46 also displayed potent anti tumour efficacy in the MDS 361 breast tumour xenograft model following daily iv dosing. A report from Venkatesan et al. outlined the synthesis and characterization of 7H pyrroloquinazolines with PI3K and mTOR activity.
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