Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies
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- 作者：Chris Dockendorff ; Marek M. Nagiec ; Michel We茂wer ; 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 ; Jos茅 R. Perez ; Stuart L. Schreiber
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：October 11, 2012
- 年：2012
- 卷：3
- 期：10
- 页码：808-813
- 全文大小：400K
- 年卷期：v.3,no.10(October 11, 2012)
- ISSN：1948-5875
文摘
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 渭M against C3H10T1/2 cells undergoing Hh-induced activation, as measured by Gli1 transcription and alkaline phosphatase induction. Studies with Patched knockout (Ptch鈥?鈥?/sup>) cells and competition studies with the Smoothened (Smo) agonists SAG and purmorphamine demonstrate that in contrast to robotnikinin, select analogues are Smo antagonists.