Unknown

Dataset Information

0

Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies.


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 ?M 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.

SUBMITTER: Dockendorff C 

PROVIDER: S-EPMC3469069 | BioStudies | 2012-01-01

REPOSITORIES: biostudies

Similar Datasets

| S-EPMC2892286 | BioStudies
2018-01-01 | S-EPMC6168716 | BioStudies
| S-EPMC7555769 | BioStudies
2019-01-01 | S-EPMC6329794 | BioStudies
1000-01-01 | S-EPMC3488104 | BioStudies
2018-05-05 | GSE111669 | GEO
2015-01-01 | S-EPMC4500289 | BioStudies
| S-EPMC3164386 | BioStudies
2018-01-01 | S-EPMC6110505 | BioStudies
2018-01-01 | S-EPMC6052211 | BioStudies