Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90.

With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973).

The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer.

Mechanistic studies of the allylic rearrangements of alpha-silyloxy allylic silanes to silyloxy vinylic silanes.

Mechanistic evidence suggests that the Lewis acid-promoted allylic rearrangement of alpha-silyloxy allylic silanes proceeds along an ionic reaction pathway involving a contact ion pair. The driving force for this transformation is alleviation of steric congestion at the allylic position of the alpha-silyloxy allylic silane and stabilization of pi cc by hyperconjugation.