Document Report Card

ID: ALA2150854

Journal: ACS Med Chem Lett

Title: Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies.

Authors: Dockendorff C, Nagiec MM, Weïwer M, Buhrlage S, Ting A, Nag PP, Germain A, Kim HJ, Youngsaye W, Scherer C, Bennion M, Xue L, Stanton BZ, Lewis TA, Macpherson L, Palmer M, Foley MA, Perez JR, Schreiber SL.

Abstract: Macrocyclic Hedgehog (Hh) pathway inhibitors have been discovered with improved potency and maximal inhibition relative to the previously reported macrocycle robotnikinin. Analogues were prepared using a modular and efficient build-couple-pair (BCP) approach, with a ring-closing metathesis step to form the macrocyclic ring. Varying the position of the macrocycle nitrogen and oxygen atoms provided inhibitors with improved activity in cellular assays; the most potent analogue was 29 (BRD-6851), with an IC(50) of 0.4 μM against C3H10T1/2 cells undergoing Hh-induced activation, as measured by Gli1 transcription and alkaline phosphatase induction. Studies with Patched knockout (Ptch(-/-)) cells and competition studies with the Smoothened (Smo) agonists SAG and purmorphamine demonstrate that in contrast to robotnikinin, select analogues are Smo antagonists.

CiteXplore: 23074541

DOI: 10.1021/ml300172p