The development of PI3K inhibitors as anticancer drugs

• Main Author: Marshall, Andrew James
• Other Authors: Rewcastle, Gordon
• Published: ResearchSpace@Auckland 2011
• Online Access: http://hdl.handle.net/2292/6440

Phosphatidylinositol 3-kinases (PI3Ks) are a lipid enzyme family that are vitally important regulators of intracellular signalling pathways which control cellular activities including cell survival, growth and proliferation. Deregulation of the PI3K signalling cascade has been observed in a broad range of human diseases including cancer, diabetes, thrombosis, immunity and inflammatory disorders. With the discovery of PI3K’s link to a variety of diseases, there has been a race to produce ATP competitive inhibitors as therapeutic agents against the Class I PI3K isozymes. Herein, compounds from two structurally distinct chemotypes were synthesised and their activity and specificity characterized against isolated Class PI3K enzymes and two cellular lines. The aryl morpholine containing pyrido[1,2-a]pyrimidines probed the requirements of the Class IA PI3K active sites through modification of the pendant C9 position. Interestingly, no compound synthesised exhibited superior activity towards the p110β enzyme than TGX-221 (1.14). The second series of compounds probed the requirements of the thiazole-linked pyrazolo[1,5-a]pyridine 4.41B, identified through scaffold hopping studies using the novel p110α selective inhibitor PIK-75 (1.34). Although 4.41B was not synthetically accessible, analogues explored alternative linkers and substitution of the 2-methyl-5-nitrobenzene ring, to investigate the effect on p110α selectivity and potency. The sulfone-pyrazole linker group in (5.5) was found to be critical, with alternative linker groups in the thiazole series SO2CH2 4.123, CH2 4.122, CHOH 4.114 and linker absent 4.108 ablating activity, while activity was retained by thiazole-CH2SO2 4.124. As the complexes between the pyrido[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine chemotypes with the active sites of p110β and p110α respectively are not known, docking simulations were performed using structural p110β models and p110α (pdb:2RD0) respectively to understand the molecular basis for the isoform selectivity exhibited by the two chemotypes. Suitable docking methods were obtained by first investigating the ability of three docking protocols GOLD, SURFLEX and AutoDock to find and correctly rank an experimentally derived conformation both retrospectively (rescoring), where the compounds were docked back into the p110γ crystal, and prospectively, where the ligands were docked into the apo p110α (2RD0).