Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies
| Autor: | Stuart L. Schreiber, Michael Foley, Andrew Germain, Willmen Youngsaye, Timothy A. Lewis, Lawrence MacPherson, Michelle Palmer, Marek M. Nagiec, Christina Scherer, Han-Je Kim, Partha P. Nag, Michel Weïwer, BenjaminZ. Stanton, Chris Dockendorff, Melissa Bennion, Amal Ting, Jose Perez, Sara J. Buhrlage, Linlong Xue |
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| Rok vydání: | 2012 |
| Předmět: |
Purmorphamine
Patched Letter Stereochemistry 010402 general chemistry 01 natural sciences Biochemistry C3H10T1/2 GLI1 Drug Discovery Mode of action Hedgehog Smoothened antagonist Sonic Hedgehog pathway biology 010405 organic chemistry Organic Chemistry Combinatorial chemistry Hedgehog signaling pathway 0104 chemical sciences 3. Good health biology.protein Alkaline phosphatase macrocycle Smoothened diversity-oriented synthesis (DOS) |
| Zdroj: | ACS Medicinal Chemistry Letters |
| ISSN: | 1948-5875 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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