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Kinch M.S.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2015

Cancer remains the second leading cause of death globally. The number of new medicines targeting cancer has grown impressively since the 1990s. On average, ten new drugs are introduced each year. Such growth has partly been achieved by emphasizing biologics and orphan indications, which account for one-quarter and one-half of new oncology drugs, respectively. The biotechnology industry likewise has become the primary driver of cancer drug development in terms of patents, preclinical and clinical research, although pharmaceutical companies are granted more FDA approvals. Many targeting strategies have been successful but recent trends suggest that kinase targets, although tractable, might be overemphasized. © 2014 Elsevier Ltd.

Kinch M.S.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2015

Neuroscience remains a great challenge and opportunity in terms of new drug discovery and development. An assessment of FDA-approved new molecular entities (NMEs) reveals a low steady rate of new FDA approvals, which is interrupted by two bursts in activity, first in the 1950s and then in the 1990s. These trends are reflected in the approvals for NMEs targeting multiple indications in this field, including seizure, Parkinson's disease and neuromuscular disorders. The majority of drugs target ion channels or G-protein-coupled receptors (GPCRs) but the mechanistic basis for many NMEs remains unclear or controversial. These trends could suggest future opportunities for success in a crucial field with considerable unmet needs. © 2015 Elsevier Ltd. All rights reserved.

Surovtseva Y.V.,Yale Center for Molecular Discovery | Jairam V.,Yale University | Salem A.F.,Yale University | Sundaram R.K.,Yale University | And 2 more authors.
Journal of the American Chemical Society | Year: 2016

Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs. These observations provide an explanation for the anticancer activity of this class of compounds, which has remained poorly understood for decades, and provide guidance for their clinical applications. This discovery was enabled by the development of the first high-throughput unbiased cellular assay to identify new small-molecule inhibitors of DSB repair. Our assay is based on the fully automated, time-resolved quantification of phospho-SER139-H2AX (γH2AX) and 53BP1 foci, two factors involved in the DNA damage response network, in cells treated with small molecules and ionizing radiation (IR). This primary assay is supplemented by robust secondary assays that establish lead compound potencies and provide further insights into their mechanisms of action. Although the cardiac glycosides were identified in an evaluation of 2366 small molecules, the assay is envisioned to be adaptable to larger compound libraries. The assay is shown to be compatible with small-molecule DNA cleaving agents, such as bleomycin, neocarzinostatin chromophore, and lomaiviticin A, in place of IR. © 2016 American Chemical Society.

Kinch M.S.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2014

Since the 1970s, biotechnology has been a key innovator in drug development. An analysis of FDA-approved therapeutics demonstrates pharmaceutical companies outpace biotechs in terms of new approvals but biotechnology companies are now responsible for earlier-stage activities (patents, INDs or clinical development). The number of biotechnology organizations that contributed to an FDA approval began declining in the 2000s and is at a level not seen since the 1980s. Whereas early biotechnology companies had a decade from first approval until acquisition, the average acquisition of a biotechnology company now occurs months before their first FDA approval. The number of hybrid organizations that arise when pharmaceutical companies acquire biotechnology is likewise declining, raising questions about the sustainability of biotechnology. © 2014 Elsevier Ltd.

Stachelek G.C.,Yale University | Peterson-Roth E.,Yale University | Liu Y.,Yale University | Fernandez R.J.,Yale University | And 7 more authors.
Molecular Cancer Research | Year: 2015

Radiotherapy and DNA-damaging chemotherapy are frequently utilized in the treatment of solid tumors. Innate or acquired resistance to these therapies remains a major clinical challenge in oncology. The development of small molecules that sensitize cancers to established therapies represents an attractive approach to extending survival and quality of life in patients. Here, we demonstrate that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. YU238259 specifically inhibits homology-dependent DNA repair, but not non-homologous end-joining, in cell-based GFP reporter assays. Treatment with YU238259 is not only synergistic with ionizing radiation, etoposide, and PARP inhibition, but this synergism is heightened by BRCA2 deficiency. Further, growth of BRCA2-deficient human tumor xenografts in nude mice is significantly delayed by YU238259 treatment even in the absence of concomitant DNA-damaging therapy. The cytotoxicity of these small molecules in repair-deficient cells results from an accumulation of unresolved DNA double-strand breaks. These findings suggest that YU238259 or related small molecules may have clinical benefit to patients with advanced BRCA2-negative tumors, either as a monotherapy or as an adjuvant to radiotherapy and certain chemotherapies. Implications: We have identified a novel series of compounds that demonstrate synthetic lethality in DNA repair-deficient cell and animal models and have strong potential for clinical translation. © 2015 American Association for Cancer Research.

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