|Publication Type||Journal Article|
|Year of Publication||2012|
|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|
|Journal||ACS medicinal chemistry letters|
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.