GDC-0449—A potent inhibitor of the hedgehog pathway

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Abstract

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.

Graphical abstract

Starting from lead compound 1, rescaffolding gave 15. Further optimization resulted in the discovery of 2-pyridyl Hh antagonist 31 (GDC-0449), which is currently in human clinical trials.

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Acknowledgments

The authors thank Martin Struble and Mengling Wong for purification of compounds, Vickie Tsui for computational support, Harvey Wong for transport studies with GDC-0449, and Mike Reich and the in vivo group for their support of PK and PK/PD studies.

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