Article

Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K

Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.33). 06/2013; 23(16). DOI: 10.1016/j.bmcl.2013.06.010
Source: PubMed

ABSTRACT PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.

0 Followers
 · 
74 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
    Nature 12/1995; 378(6559):785-9. DOI:10.1038/378785a0 · 42.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Phosphoinositide 3-kinases (PI3Ks) are central to the control of cell growth, proliferation and survival, and drive the progression of tumours by activating phosphoinositide-dependent kinase, protein kinase B and the target of rapamycin. Other downstream effectors link PI3K to cell motility and the control of cardiovascular parameters. Current knowledge indicates that PI3Ks might qualify as drug targets for the treatment of cancer, chronic inflammation, allergy and cardiovascular failure. However, PI3Ks also modulate vital processes such as metabolic control and nutrient uptake. Here, mechanistic data and mouse phenotypic analyses are summarised, and the possible success of therapeutic inhibition of distinct PI3K isoforms is discussed.
    Trends in Pharmacological Sciences 08/2003; 24(7):366-76. DOI:10.1016/S0165-6147(03)00163-9 · 9.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PI3 Kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration, and differentiation. The PI3 kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations, and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe a novel series of PI3K inhibitors sharing a pyrimidine core and showing significant potency against class I PI3 kinases in the biochemical assay and in cells. The discovery, synthesis and SAR of this chemotype are described.
    Bioorganic & medicinal chemistry letters 10/2010; 20(23):6895-8. DOI:10.1016/j.bmcl.2010.10.021 · 2.33 Impact Factor