Neel Kumar Anand

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. 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.

Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR).

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

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.

Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors.

The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.

Chapter 17 Emerging Therapies Based on Inhibitors of Phosphatidyl-Inositol-3-Kinases

Publisher Summary Phosphoinositide kinases (PIKs) have been an area of intense investigation due to the crucial role of members of this class in various signal transduction-mediated events. As the basic biology of the PIKs has become better understood, their roles in various patho-physiologies such as cancer, inflammation, and cardiovascular disease are also becoming clearer, leading to the development of agents targeting the function of these kinases as new modalities for the treatment of a number of disease states. The phosphoinositide kinases (PIKs) catalyze the conversion of phosphatidyl inositol (PI) to various phosphoinositides. Of particular importance is the phosphoinositide3-kinase (PI3K). This chapter illustrates PI3K signaling pathways. The activation of PI3Ks results in the formation of PIP3, which recruits the kinases3-phosphoinositide dependent kinase (PDK) and protein kinase B (PKB, or AKT) to the cell membrane. AKT is activated through phosphorylation by the membrane-bound PDK. The activation of AKT effects the amyriad of downstream processes, including the modulation of numerous proteins such as mTOR, GSK3, forkhead, NF- k B transcription factors, and eNOS, which are involved in processes such as metabolism, cell growth, survival, and angiogenesis.

Raf modulators and methods of use

Exelixis claims a series of RAF kinase inhibitors based on a 3-oxo-2,3-dihydro-1H-isoindol-1-yl core structure. Both the chemical matter and the biochemical target appear to be new for Exelixis, and many examples have IC50 values < 100 nM. These compounds are claimed to have the potential to treat diseases that are associated with uncontrolled, abnormal and/or unwanted cellular activities such as cancer.

Pyrazolopyrimidines as dual Akt/p70S6K inhibitors.

Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.