Vertex Pharmaceuticals, Inc.

Brian J Hare

Mark Thomas Miller

Jinglan Zhou

Sara Sabina Hadida Ruah

Guy W Bemis

Corey Don Anderson

Fredrick Van Goor

Peter Grootenhuis

Thomas Cleveland

Bryan A Frieman

William Markland

Timothy Richard Coon

Prasuna Paraselli

Fabrice Pierre

Jeremy J Clemens

Weichao George Chen

David A Newsome

Marina S Penney

Diane M Boucher

Shawn M Hillier

Lovorka Swenson

W Patrick Walters

Sara E Swift

Wanjung Tsai

Marc Jacobs

Paul R Caron

Shu-Pei Wu

Alexander Wolfgang Krug

Ifeatu Egbuna

Navita Mallalieu

Jason Mccartney

Bartlomiej Borek

Sarah M Robertson

Tim Young

Described herein are methods of treating a proliferative disease in a subject by administering a DNA-damaging agent and between about 8 and about 48 hours later administering to the subject a DNA-PK inhibitor. Exemplary DNA-PK inhibitors are represented by Formula (B-I): and by pharmaceutically acceptable salts thereof, wherein R, Q, Ring A, and Ring B are as defined herein.

Method for treating cancer using a combination of DNA-damaging agents and DNA-PK inhibitors

This application describes methods of inhibiting APOL1 and treating APOL1-mediated kidney diseases comprising administering Compound I and/or a pharmaceutically acceptable salt thereof. The application also describes pharmaceutical compositions comprising Compound I and/or a pharmaceutically acceptable salt thereof.

Methods of treating APOL-1 dependent focal segmental glomerulosclerosis

Described herein are methods of treating a proliferative disease in a subject by administering a DNA-damaging agent and between about 8 and about 48 hours later administering to the subject a DNA-PK inhibitor. Exemplary DNA-PK inhibitors are represented by Formula (B-I): and by pharmaceutically acceptable salts thereof, wherein R, Q, Ring A, and Ring B are as defined herein. 

Computer-based methods for modeling complex formation between a query ligand and a target macromolecule are described herein. The methods can include, for example, providing a structural model of a query ligand and a structural model of a target macromolecule; identifying a substructure of the query ligand; identifying comparison ligands in a set of 3-D structural models that each share an identical substructure with the query ligand, wherein each 3-D structural model comprises a comparison ligand and a comparison macromolecule, and wherein the comparison macromolecule has structural features homologous to the target macromolecule; mapping spatial relationships between the substructure atoms of the query ligand and the comparison ligand such that corresponding atoms are identified; assigning atomic coordinates to the corresponding atoms of the query ligand; and generating one or more output models, each model comprising a 3-D structural model of the query ligand substructure and the target macromolecule. Related articles and apparatuses are also described.

Method of modeling complex formation between a query ligan and a target molecule

The present invention relates to the X-ray analysis of crystalline molecules or molecular complexes of human Pim-1. The present invention also relates to Pim-1-like binding pockets. The present invention provides a computer comprising a data storage medium encoded with the structure coordinates of such binding pockets. This invention also relates to methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. In addition, this invention relates to methods of using the structure coordinates to screen for and design compounds, including inhibitory compounds, that bind to Pim-1 protein, Pim-1 protein complexes, or homologues thereof. The invention also relates to crystallizable compositions and crystals comprising Pim-1 protein, Pim-1 protein complexes with adenosine, staurosporine or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one and methods to produce these crystals.

Crystal structure of human Pim-1 kinase protein complexes and binding pockets thereof, and uses thereof in drug design

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Arlington, MA, United States of America

Brian J Hare