Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies
Year: 2012
Type: article
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.
Source: ACS Medicinal Chemistry Letters
DOI: 10.1021/ml300172p
Authors: Chris Dockendorff, 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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W1979685901