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Petrocchi A.,University of Texas M. D. Anderson Cancer Center | Leo E.,University of Texas M. D. Anderson Cancer Center | Leo E.,Cancer Research Technology Discovery Laboratories | Reyna N.J.,University of Texas M. D. Anderson Cancer Center | And 16 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification of IACS-4759 (compound 5), a sub-nanomolar inhibitor of MTH1 with excellent cell permeability and good metabolic stability in microsomes. This compound robustly inhibited MTH1 activity in cells and proved to be an excellent tool for interrogation of the utility of MTH1 inhibition in the context of oncology. © 2016 Elsevier Ltd


Rosenberg L.H.,Scripps Research Institute | Rosenberg L.H.,Cancer Research Technology Discovery Laboratories | Lafitte M.,Scripps Research Institute | Quereda V.,Scripps Research Institute | And 12 more authors.
Science Translational Medicine | Year: 2015

Identification of specific drivers of human cancer is required to instruct the development of targeted therapeutics. We demonstrate that CSNK1D is amplified and/or overexpressed in human breast tumors and that casein kinase 1d (CK1δ) is a vulnerability of human breast cancer subtypes overexpressing this kinase. Specifically, selective knockdown of CK1δ, or treatment with a highly selective and potent CK1δ inhibitor, triggers apoptosis of CK1δ-expressing breast tumor cells ex vivo, tumor regression in orthotopic models of triple-negative breast cancer, including patient-derived xenografts, and tumor growth inhibition in human epidermal growth factor receptor 2-positive (HER2+) breast cancer models. We also show that Wnt/δ-catenin signaling is a hallmark of human tumors overexpressing CK1δ, that disabling CK1δ blocks nuclear accumulation of β-catenin and T cell factor transcriptional activity, and that constitutively active δ-catenin overrides the effects of inhibition or silencing of CK1δ. Thus, CK1δ inhibition represents a promising strategy for targeted treatment in human breast cancer with Wnt/δ-catenin involvement.


Hammonds T.,Cancer Research Technology Discovery Laboratories
Future Medicinal Chemistry | Year: 2015

Industrial pharmaceutical companies (Pharma) share a common goal with academic scientists (Academia) in that they wish to create an environment in which patients are treated for diseases with ever more effective therapies. As disease biology has proven to be ever more complex and money and new drugs are becoming more elusive, Pharma and Academia are reaching toward each other with ever greater collaborative intent. There are a growing number of collaboration models that allow scientists to work together and profit from the creation of new drugs. Here I give a personal view of how we came to where we are, present an overview of a number of these models and look to the future in terms of running successful discovery alliances. © 2015 Future Science Ltd.


Petrocchi A.,University of Texas M. D. Anderson Cancer Center | Leo E.,Cancer Research Technology Discovery Laboratories | Reyna N.J.,University of Texas M. D. Anderson Cancer Center | Hamilton M.M.,University of Texas M. D. Anderson Cancer Center | And 14 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification of IACS-4759 (compound 5), a sub-nanomolar inhibitor of MTH1 with excellent cell permeability and good metabolic stability in microsomes. This compound robustly inhibited MTH1 activity in cells and proved to be an excellent tool for interrogation of the utility of MTH1 inhibition in the context of oncology. © 2016 Elsevier Ltd.


Saunders V.C.,Scripps Research Institute | Lafitte M.,Scripps Research Institute | Adrados I.,Scripps Research Institute | Quereda V.,Scripps Research Institute | And 5 more authors.
Molecular Pharmacology | Year: 2015

Glioblastoma multiforme (GBM) is the most aggressive and common form of adult brain cancer. Current therapeutic strategies include surgical resection, followed by radiotherapy and chemotherapy. Despite such aggressive multimodal therapy, prognosis remains poor, with a median patient survival of 14 months. A proper understanding of the molecular drivers responsible for GBM progression are therefore necessary to instruct the development of novel targeted agents and enable the design of effective treatment strategies. Activation of the c-Jun N-terminal kinase isoform 2 (JNK2) is reported in primary brain cancers, where it associates with the histologic grade and amplification of the epidermal growth factor receptor (EGFR). In this manuscript, we demonstrate an important role for JNK2 in the tumor promoting an invasive capacity of EGFR variant III, a constitutively active mutant form of the receptor commonly found in GBM. Expression of EGFR variant III induces transactivation of JNK2 in GBM cells, which is required for a tumorigenic phenotype in vivo. Furthermore, JNK2 expression and activity is required to promote increased cellular invasion through stimulation of a hepatocyte growth factor-c-Met signaling circuit, whereby secretion of this extracellular ligand activates the receptor tyrosine kinase in both a cell autonomous and nonautonomous manner. Collectively, these findings demonstrate the cooperative and parallel activation of multiple RTKs in GBM and suggest that the development of selective JNK2 inhibitors could be therapeutically beneficial either as single agents or in combination with inhibitors of EGFR and/or c-Met. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

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