2. Academic Validation
  3. Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies

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

Affiliation

  • 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.

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