Robert L. Hudkins’s research while affiliated with West Chester University and other places

The c-Jun NH2-terminal kinase (JNK) signaling pathway is central to the cell response to stress, inflammatory signals, and toxins. While selective inhibitors are known for JNKs and for various upstream MAP3Ks, no selective inhibitor is reported for MKK7--one of two direct MAP2Ks that activate JNK. Here, using covalent virtual screening, we identify selective MKK7 covalent inhibitors. We optimized these compounds to low-micromolar inhibitors of JNK phosphorylation in cells. The crystal structure of a lead compound bound to MKK7 demonstrated that the binding mode was correctly predicted by docking. We asserted the selectivity of our inhibitors on a proteomic level and against a panel of 76 kinases, and validated an on-target effect using knockout cell lines. Lastly, we show that the inhibitors block activation of primary mouse B cells by lipopolysaccharide. These MKK7 tool compounds will enable better investigation of JNK signaling and may serve as starting points for therapeutics.

Introduction: Elevated lipogenesis has been associated with a variety of diseases including obesity, cancer and nonalcoholic fatty liver disease (NAFLD). Fatty acid synthase (FASN) plays a pivotal role in de novo lipogenesis, making this multi-catalytic protein an attractive target for therapeutic intervention. Recently, the first FASN inhibitor successfully advanced through the drug development process and entered clinical evaluation in oncology. Areas covered: This review discusses the biological roles of FASN in three prominent disease areas: cancer, obesity-related disorders and non-alcoholic fatty liver disease. Recent advances in drug discovery strategies and design of newer FASN inhibitors are also highlighted. Expert opinion: Despite the abundance of evidence linking the lipogenic pathway to cancer, progression of FASN-targeted molecules has been rather slow and challenging and no compounds have moved past the preclinical phase. The landscape has recently changed with the recent advancement of the first FASN inhibitor into clinical evaluation for solid tumors. Needless to say, the successful translation into the clinical setting will open opportunities for expanding the therapeutic utility of FASN inhibitors not just in oncology but in other diseases associated with elevated lipogenesis such as obesity, type 2 diabetes, and NAFLD.

At the drug discovery stage, it is important to understand the design concepts of a CNS drug compared to a non-CNS drug. Previously we published on ideal CNS drug space and defined in detail the physicochemical property space distribution of CNS and non-CNS oral drugs, the application of radar charting (a graphical representation of multiple physicochemical properties used during CNS lead optimization) and a recursive partition classification tree to differentiate between CNS and non-CNS drugs. The objective of the present study was to further the understanding of differentiations between CNS and non-CNS oral drugs into the development and application of an effective CNS algorithm TEMPO (Technically Extended Multiparameter Optimization). In the current multiparameter method we identified eight physicochemical properties critical for accurately assessing CNS druggability: (i) number of basic amines, (ii) carbon-hetero atom (non-C, non-H) ratio, (iii) number of aromatic rings, (iv) number of chains, (v) number of rotatable bonds, (vi) number of H-acceptors, (vii) computed octanol/water partition coefficient, AlogP, and (viii) number of nonconjugated C-atoms in non-aromatic rings. A significant advantage of the CNS-TEMPO tool is the extension of the multiparameter approach to generate physically realistic weight factors, and the application of limits on both sides of the computed property space range to overcome some of the shortcomings of the CNS-MPO scoring function, and the fact MPO made no attempt to differentiate the scores of CNS and non-CNS drugs. As demonstrated in this paper, CNS-TEMPO significantly outperformed CNS-MPO and Schrodinger QikProp in assessing CNS druggability space and has been applied extensively to support CNS lead optimization.

The present invention is directed to novel multicyclic molecules that mediate enzymatic activity. In particular, the compounds may be effective in the treatment of diseases or disease states related to the activity of PARP, VEGFR2, and MLK3 enzymes, including, for example, neurodegenerative diseases, inflammation, ischemia, and cancer.

The present invention provides compounds of formula I: their use as H3 antagonists/inverse agonists, processes for their preparation, and pharmaceutical compositions thereof.

The oncogenic receptor tyrosine kinases AXL and c-Met are over-expressed and constitutively activated in a variety of human cancers. Activation of these receptors contributes to multiple steps in tumor progression by promoting cancer cell migration and invasion, enhancing tumor angiogenesis, facilitating cancer cell survival and tumor growth, and contributing to tumor resistance to several chemotherapy and molecular-targeted therapeutic agents. CEP-40783 is an orally active, potent and selective AXL and c-Met kinase inhibitor, with enzyme IC50 values of 7 nM and 12 nM, respectively. In AXL-transfected 293GT cells, CEP-40783 was 27-fold more active compared to recombinant enzyme with an IC50 value of 0.26 nM. Comparably high cellular potency was observed in NCI-H1299 human NSCL cells. CEP-40783 also demonstrated superior activity against c-Met in GTL-16 cells (IC50 = 6 nM). The increased inhibitory activity of CEP-40783 in cells could be attributed to its extended residence time on both AXL and c-Met, consistent with a Type II mechanism. The prolonged residence time of CEP-40783 at the target may provide for improved in vivo efficacy, selectivity and therapeutic index. Additionally, CEP-40783 showed high kinome selectivity against 298 kinases with an S90 of 0.04 (fraction of kinases showing >90% inhibition at 1 µM). In PK/PD studies, CEP-40783 showed dose- and time-dependent inhibition of AXL phosphorylation using NCI-H1299 NSCL xenografts with ∼80% target inhibition at 0.3 mg/kg 6 h post dose and complete target inhibition to >90% inhibition at 1 mg/kg between 6-24 h, while a 10 mg/kg po dose resulted in complete AXL inhibition up to 48 h post dosing. In AXL/NIH3T3 xenografts, 0.3 mg/kg po resulted in complete tumor regressions. CEP-40783 was also efficacious in reducing spontaneous lymph node and pulmonary metastatic tumor burden in the MDA-MB-231-luc and 4T1-luc orthotopic breast cancer models, respectively, at 10 and 30 mg/kg po. PK/PD evaluation of the c-Met activity of CEP-40783 (10, 30, 55 mg/kg po qdX5d) showed significant to complete inhibition of c-Met phosphorylation in GTL-16 gastric carcinoma xenografts. Efficacy studies in GTL-16 xenografts demonstrated significant anti-tumor efficacy (tumor stasis and regressions) at 10 and 30 mg/kg po. In EBC-1 NSCL xenografts, administration of CEP-40783 (3, 10 and 30 mg/kg, po qd) resulted in dose-related efficacy, with tumor stasis at 3 mg/kg, tumor regressions and >96% TGI at 10 mg/kg. In all studies CEP-40783 was well tolerated with no compound-related body weight loss. CEP-40783 demonstrated potent AXL and c-Met pharmacodynamic and anti-tumor efficacy in established tumor xenograft models, having potential therapeutic utility in multiple human tumor types in which c-Met and AXL activity play a critical role in tumor formation, local invasion and metastasis. Studies in primary human tumorgrafts are in progress. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C275. Citation Format: Sheila Miknyoczki, Mangeng Cheng, Robert Hudkins, Thelma Angeles, Lisa Aimone, Jean Husten, Jie Qian, Seetha Murthy, Thomas Conners, Robert Bendesky, Amy Landis, Jennifer Grobelny, Hong Chang, Bruce Dorsey, Mark Ator, Bruce Ruggeri. CEP-40783: A potent and selective AXL/c-Met inhibitor for use in breast, non-small cell lung (NSCLC), and pancreatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C275.

The oncogenic receptor tyrosine kinases (RTK) AXL and c-Met are over-expressed and constitutively activated in a variety of human cancers. Activation of these receptors contributes to multiple steps in tumor progression, including the epithelial-mesenchymal transition (EMT) by which cancer cells escape to form metastases and frequently develop resistance to a variety of agents, most notably to epidermal growth factor receptor (EGFR) targeted therapies. CEP-40783 is an orally-active, nanomolar potent and highly kinase-selective Type II inhibitor of the AXL and c-Met RTK in drug development. In the current study, five Champions human TumorGraft™ models of NSCLC expressing constitutively activated AXL and/or c-Met were used to determine the anti-tumor efficacy of single agent CEP-40783 compared to paclitaxel and the EGFR inhibitor, erlotinib (Genentech-Roche; OSI Pharmaceuticals). Champions Oncology has developed an innovative platform that utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor and results in more rigorous and clinically relevant models for drug discovery. Previous reports have shown the correlation between responsiveness observed in Champions TumorGraft™ models and clinical responses of the patients from which the models were derived. Mice bearing established Champions TumorGrafts™ were treated orally with 10 mg/kg and 30 mg/kg qd of CEP-40783 for 10 to 34 days (until control tumors achieved >1000 mm3 volume) and anti-tumor efficacy and tolerability were evaluated. In 3/5 (60%) of the tumor models, CEP-40783 showed in vivo efficacy, including tumor regressions, significantly superior to that achieved with an optimal regimen of paclitaxel. In 4/4 (100%) of the erlotinib-insensitive tumor models, CEP-40783 demonstrated significant efficacy (66 to 118% TGI) compared to the control group at the 30 mg/kg dose. Additionally, CEP-40783 in combination with erlotinib demonstrated superior anti-tumor efficacy compared to CEP-40783 and erlotinib single agents in the one erlotinib-sensitive model evaluated. CEP-40783 as a single agent and in combination with erlotinib was well tolerated. Retrospective bioinformatics analyses are planned to determine potential signatures of response and resistance to CEP-40783. These results demonstrate that CEP-40783 shows superior efficacy alone and in combination with erlotinib in Champions TumorGraft™ models of NSCLC compared to SOC agents and supports the development of CEP-40783 for the treatment of erlotinib-resistant NSCLC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C272. Citation Format: Jay A. Friedman, Rodney Donaldson, Sheila Miknyoczki, Mangeng Cheng, Robert Hudkins, Bruce Dorsey, Mark Ator, Thelma Angeles, Bruce Ruggeri, Elizabeth Bruckheimer. Antitumor activity of the dual AXL/c-Met inhibitor CEP-40783 in Champions primary TumorGraft™ models of human non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C272.