| Summary: | 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).
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