Kumar Thakur

3-Amido-4-anilinocinnolines as a novel class of CSF-1R inhibitor

3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data.

Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo.

In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.

Potent and Selective Inhibitors of CK2 Kinase Identified through Structure-Guided Hybridization

In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.

Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507.

The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.

Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens

Negamycin is a natural product with antibacterial activity against a broad range of Gram-negative pathogens. Recent revelation of its ribosomal binding site and mode of inhibition has reinvigorated efforts to identify improved analogues with clinical potential. Translation-inhibitory potency and antimicrobial activity upon modification of different moieties of negamycin were in line with its observed ribosomal binding conformation, reaffirming stringent structural requirements for activity. However, substitutions on the N6 amine were tolerated and led to N6-(3-aminopropyl)-negamycin (31f), an analogue showing 4-fold improvement in antibacterial activity against key bacterial pathogens. This represents the most potent negamycin derivative to date and may be a stepping stone toward clinical development of this novel antibacterial class.

Target deconvolution efforts on Wnt pathway screen reveal dual modulation of oxidative phosphorylation and SERCA2

Wnt signaling is critical for development, cell proliferation and differentiation, and mutations in this pathway resulting in constitutive signaling have been implicated in various cancers. A pathway screen using a Wnt‐dependent reporter identified a chemical series based on a 1,2,3‐thiadiazole‐5‐carboxamide (TDZ) core with sub‐micromolar potency. Herein we report a comprehensive mechanism‐of‐action deconvolution study toward identifying the efficacy target(s) and biological implication of this chemical series involving bottom‐up quantitative chemoproteomics, cell biology, and biochemical methods. Through observing the effects of our probes on metabolism and performing confirmatory cellular and biochemical assays, we found that this chemical series inhibits ATP synthesis by uncoupling the mitochondrial potential. Affinity chemoproteomics experiments identified sarco(endo)plasmic reticulum Ca2+‐dependent ATPase (SERCA2) as a binding partner of the TDZ series, and subsequent validation studies suggest that the TDZ series can act as ionophores through SERCA2 toward Wnt pathway inhibition.

Abstract 2461: Design and synthesis of AZD3463, a novel orally bioavailable dual ALK and IGF1R inhibitor, inhibits growth of crizotinib resistance cell lines with multiple mechanisms of acquired resistance.

Although the ALK inhibitor crizotinib has clinical efficacy in selected ALK positive NSCLC patients, the majority of patients who initially respond eventually relapse. Several mechanisms of resistance have been proposed including amplification, resistance mutations, as well as alternative pathway drivers including EGFR, cKIT and IGF1R. We report here the discovery of a novel scaffold of ALK inhibitors and optimization effort that led to the discovery of AZD3463 a novel dual in vivo active ALK and IGF1R inhibitor. An in house subset screening of kinase inhibitors and de novo studies identified 4-(1H-indol-3-yl)pyrimidin-2-amine analogs as potent ALK inhibitors. Modeling studies were utilized to guide the SAR strategy around the aminopyrimidine group which afforded several lead compounds. Early SAR efforts quickly determined that smaller substituents, chloro and methyl, were optimal in the C5 position of the pyrimidine, and that aniline is preferred over several other amino heterocycles investigated. Parallel medicinal chemistry strategies were executed for the optimization of the aniline and indole. These studies suggested that a 2,4-substituted aniline provided optimal potency and selectivity in conjunction with a variety of heterocycles in C4 position of the pyrimdine. Cyclic amines in the C4 position of the aniline led to simultaneous improvement of potency and metabolic stability. The inhibition of IGF1R in vitro was maintained and modulation of glucose levels in vivo was observed with the optimized compounds and AZD3463. AZD3463 demonstrated superior potency to crizotinib in vivo (H3122 PD unbound EC50=0.16 nM). In summary, detailed SAR studies were executed on the 4-(1H-indol-3-yl)pyrimidin-2-amine template that produced potent inhibitors of ALK with improved physical chemical and ADME properties, and identified AZD3463, a novel equipotent ALK and IGF1R inhibitor, potent in ALK-driven preclinical models and in a variety of crizotinib-resistant models. We present herein the design and synthesis of AZD3463 as well as its overall properties. Citation Format: Jamal C. Saeh, Bin Yang, Tim Pontz, Kumar Thakur, Bo Peng, Lisa Drew, Caroline Rivard, Dan Widzowski, Jane Cheng, Douglas Ferguson, Brenda McDermott, Minhui Shen, John McNulty, Ryohei Katayama, Jeffrey Engleman, Alice Shaw, Daniel Russell, Graeme Smith. Design and synthesis of AZD3463, a novel orally bioavailable dual ALK and IGF1R inhibitor, inhibits growth of crizotinib resistance cell lines with multiple mechanisms of acquired resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2461. doi:10.1158/1538-7445.AM2013-2461