ABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/therapeutic use , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Phthalic Acids/chemistry , Phthalic Acids/therapeutic use , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Azabicyclo Compounds/pharmacokinetics , Azabicyclo Compounds/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Discovery , HSP90 Heat-Shock Proteins/metabolism , Humans , Mice , Models, Molecular , Neoplasms/metabolism , Neoplasms/pathology , Phthalic Acids/pharmacokinetics , Phthalic Acids/pharmacologyABSTRACT
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. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.
ABSTRACT
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.