Dataset Information

Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology.

ABSTRACT: Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of antitumor agents selectively targeting the TYRO3, AXL, and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of fragments in structural environments (FRASE), distills relevant chemical information from structural and chemogenomic databases to assemble a three-dimensional inhibitor structure directly in the protein pocket. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines, including acute lymphoblastic and myeloid leukemia (ALL/AML) and nonsmall cell lung cancer (NSCLC). Structural rationale underlying the approach was corroborated by X-ray crystallography. The lead compound demonstrated potent target inhibition in a pharmacodynamic study in leukemic mice.

SUBMITTER: Da C

PROVIDER: S-EPMC6894422 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology.

Da Chenxiao C Zhang Dehui D Stashko Michael M Vasileiadi Eleana E Parker Rebecca E RE Minson Katherine A KA Huey Madeline G MG Huelse Justus M JM Hunter Debra D Gilbert Thomas S K TSK Norris-Drouin Jacqueline J Miley Michael M Herring Laura E LE Graves Lee M LM DeRyckere Deborah D Earp H Shelton HS Graham Douglas K DK Frye Stephen V SV Wang Xiaodong X Kireev Dmitri D

Journal of the American Chemical Society 20190920 39

Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of antitumor agents selectively targeting the TYRO3, AXL, and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of fragments in structural environments (FRASE), distills relevant chemical information from structur ...[more]

PMID: 31497954

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Project description:IntroductionDue to the COVID-19 crisis or any other mass casualty situation it might be necessary to give artificial ventilation to many affected patients. Contrarily, the worldwide availability of emergency ventilators is still a shortage, especially in developing countries.MethodsModes of artificial ventilation were compared and the most safe, easy to use, and lung protecting principle was optimized to fit all requirements of both emergency ventilation and cost-effective mass production.ResultsThe presented research results describe a simplified device for a pressure-controlled ventilation which works without electricity according to a known principle. Just pressurized gas and a patient connection is required. The device enables the control of basic ventilator parameters such as peak inspiratory pressure, positive end-expiratory pressure and the ventilation frequency. Further, the device is semiadaptive to the patient's lung stiffness and automatically maintains minute volume through frequency adjustment. The machine can be manufactured by turning, milling and drilling and needs purchased components with costs less than 100 USD. A sterilization and thus a reuse is possible.DiscussionThe presented development does not describe a ready-to-purchase ventilator, it rather outlines a refined working principle for emergency ventilation and its easiest methods of production with a minimum of requirements. The presented research aims on providing an open-source guideline for production of an emergency ventilator using worldwide available methods and thus should inspire local researchers to do a reverse engineering and eventually to put it into operation following country-specific regulations. For long-term ventilation exceeding emergency purposes, a monitoring of alarms for disconnection and violation of desired ventilator parameters should be established. The ventilator is limited to a fixed ratio between PIP and PEEP. Moreover, the ventilation frequency depends on two parameters, which needs some training. Nevertheless, the ventilator provides basic features to enable an emergency ventilation with minimal prerequisites.

Dataset Information

Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology.

Publications

Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology.

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