Dyax Corporation

Vertex Pharmaceuticals, Inc.

Protein Engineering Corporation

William Markland

Robert Charles Ladner

Arthur Charles Ley

Rachel B Kent

Bruce Lindsay Roberts

Sonia Kosow Guterman

Keith P Wilson

Michael Su

David A Newsome

Xiaoling Xie

Yong Gu

Marina S Penney

Diane M Boucher

Brian J Hare

Paul R Caron

Wanjung Tsai

Shawn M Hillier

Edward Fox

Sonia Kosow Gutterman

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

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. 

This invention provides: novel protein homologous of a Kunitz domain, which are capable of binding kallikrein; polynucleotides that encode such novel proteins; and vectors and transformed host cells containing these polynucleotides.

Kallikrein-binding 'kunitz domain' proteins and analogues thereof

This invention features novel proteins that are homologous to the first Kunitz domain (K1) of lipoprotein-associated coagulation inhibitor (LACI), and are capable of inhibiting plasmin and nucleic acids encoding these proteins. The invention also features the use of such proteins in therapeutic, diagnostic, and clinical methods.

Nucleic acids encoding polypeptide inhibitors of human plasmin derived from the Kunitz domains

Kallikrein-binding 'Kunitz domain' proteins and analogues thereof

The present invention relates to molecules and molecular complexes which comprise the active site binding pockets of JNK3 or close structural homologues of the active site binding pockets.

Crystallization of C-Jun N-Terminal Kinase 3 (JNK3)

Inhibitors of human plasmin derived from the Kunitz domains

In order to obtain a novel binding protein against a chosen target, DNA molecules, each encoding a protein comprising one of a family of similar potential binding domains and a structural signal calling for the display of the protein on the outer surface of a chosen bacterial cell, bacterial spore or phage (genetic package) are introduced into a genetic package. The protein is expressed and the potential binding domain is displayed on the outer surface of the package. The cells or viruses bearing the binding domains which recognize the target molecule are isolated and amplified. The successful binding domains are then characterized. One or more of these successful binding domains is used as a model for the design of a new family of potential binding domains, and the process is repeated until a novel binding domain having a desired affinity for the target molecule is obtained. In one embodiment, the first family of potential binding domains is related to bovine pancreatic trypsin inhibitor, the genetic package is M13 phage, and the protein includes the outer surface transport signal of the M13 gene III protein.

Directed evolution of novel binding proteins

The invention relates, in part, to a library of chimeric proteins, each chimeric protein including a mini-protein between about eight and about forty amino acids long, wherein the mini-protein has a single disulfide bond formed by a pair of invariant cysteines and has only two cysteines. The chimeric protein also includes at least a portion of an outer surface protein of a genetic package, wherein the chimeric protein is displayed on the outer surface of the genetic package. The invention also includes, in part, a mixture of nucleic acids that encode a library of the invention. The invention also includes, in part, a process for identifying proteins with a desired binding activity against a target, the process including screening a library of chimeric proteins of the invention; and identifying the chimeric protein. The invention, in part, also includes chimeric proteins expressed by a library of the invention.

Directed evolution of disulfide-bonded micro-proteins

The present invention relates to a data storage medium encoded with the corresponding structure coordinates of molecules and molecular complexes which comprise the active site-binding pockets of JNK3. A computer comprising such data storage material is capable of displaying such molecules and molecular complexes, or their structural homologues, as a graphical three-dimensional representation on a computer screen. 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 and design compounds, including inhibitory compounds, that bind to JNK3 or homologues thereof. This invention also relates to molecules and molecular complexes which comprise the active site binding pockets of JNK3 or close structural homologues of the active site binding pockets.

Methods of designing inhibitors for JNK kinases

Method of recovering a nucleic acid encoding a proteinaceous binding domain which binds a target material

Mutants of Kunitz domain 1 (ITI-D1) of human inter-&#x3b1;-trypsin inhibitor (ITI), are useful as inhibitors of human neutrophil elastase. Mutants characterized by one or more of the following substitutions (numbered to correspond to bovine pancreatic trypsin inhibitor, the archetypal Kunitz domain) are of particular interest: (a) Val15 or Ile15, (b) Ala16, (c) Phe18, (d) Pro19, (e) Arg1, (f) Pro2, and/or (g) Phe4.

Growing community of inventors

Southborough, MA, United States of America

William Markland