1396152-06-9Relevant articles and documents
Macrocyclic hedgehog pathway inhibitors: Optimization of cellular activity and mode of action studies
Dockendorff, Chris,Nagiec, Marek M.,Weiwer, Michel,Buhrlage, Sara,Ting, Amal,Nag, Partha P.,Germain, Andrew,Kim, Han-Je,Youngsaye, Willmen,Scherer, Christina,Bennion, Melissa,Xue, Linlong,Stanton, Benjamin Z.,Lewis, Timothy A.,MacPherson, Lawrence,Palmer, Michelle,Foley, Michael A.,Perez, Jose R.,Schreiber, Stuart L.
, p. 808 - 813 (2013/01/15)
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 IC50 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.
