2. Academic Validation
  3. Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors

Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors

  • J Med Chem. 2012 Jun 14;55(11):5291-310. doi: 10.1021/jm300276x.
Mark A Ashwell 1,  Jean-Marc Lapierre,  Christopher Brassard,  Karen Bresciano,  Cathy Bull,  Susan Cornell-Kennon,  Sudharshan Eathiraj,  Dennis S France,  Terence Hall,  Jason Hill,  Eoin Kelleher,  Sampada Khanapurkar,  Darin Kizer,  Steffi Koerner,  Jeff Link,  Yanbin Liu,  Sapna Makhija,  Magdi Moussa,  Nivedita Namdev,  Khanh Nguyen,  Robert Nicewonger,  Rocio Palma,  Jeff Szwaya,  Manish Tandon,  Uma Uppalapati,  David Vensel,  Laurie P Volak,  Erika Volckova,  Neil Westlund,  Hui Wu,  Rui-Yang Yang,  Thomas C K Chan
Affiliations

Affiliation

  • 1 ArQule Inc., 19 Presidential Way, Woburn, Massachusetts 01801, United States.
PMID: 22533986 DOI: 10.1021/jm300276x
Abstract

This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.

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