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

  • ACS Med Chem Lett. 2012 Oct 11;3(10):808-813. doi: 10.1021/ml300172p.
Chris Dockendorff  1 ,  Marek M Nagiec ,  Michel Weïwer ,  Sara Buhrlage ,  Amal Ting ,  Partha P Nag ,  Andrew Germain ,  Han-Je Kim ,  Willmen Youngsaye ,  Christina Scherer ,  Melissa Bennion ,  Linlong Xue ,  Benjamin Z Stanton ,  Timothy A Lewis ,  Lawrence Macpherson ,  Michelle Palmer ,  Michael A Foley ,  José R Perez ,  Stuart L Schreiber
Affiliations
  • 1. Chemical Biology Platform and Probe Development Center and Howard Hughes Medical Institute, Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
PMID: 23074541 DOI: 10.1021/ml300172p
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.