Cancer Research Technology Limited

Kudos Pharmaceuticals Limited

Pfizer Corporation

Vertex Pharmaceuticals, Inc.

The University of Newcastle Upon Tyne

Nicola Curtin

Niall Morrison Barr Martin

Bernard Thomas Golding

Graeme Cameron Murray Smith

Roger John Griffin

David Richard Newell

Ian Robert Hardcastle

Hilary Alan Calvert

Laurent Jean Martin Rigoreau

Keith Allan Menear

Marc Geoffrey Hummersone

Paul Workman

Florence Irene Raynaud

Bernard Paul Nutley

Xiao-ling Fan Cockcroft

Kappusamy Saravanan

Philip Michael Reaper

Tao Chen

John Robert Pollard

Thomas Helleday

Vincent Junior Ming-lai Loh

Susanna Falcon

Fiona Middleton

Mark Frigerio

Marine Desage-El Murr

The present relates to methods for detecting DNA damage in subjects treated with an ATR inhibitor. More specifically, this invention relates to a method for measuring changes in levels of &#x3b3;H2AX and/or pChk1in, e.g., surrogate tissue cells, following ex vivo stimulation with a DNA damaging agent.

Method for measuring ATR inhibition mediated increases in DNA damage

A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: Rand Rare independently selected from hydrogen, an optionally substituted Calkyl group, Cheterocyclyl group, or Caryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; Q is &#x2014;NH&#x2014;C(&#x2550;O)&#x2014; or &#x2014;O&#x2014;; Y is an optionally substituted Calkylene group; X is selected from SRor NRR, wherein, R, or Rand Rare independently selected from hydrogen, optionally substituted Calkyl, Caryl, or Cheterocyclyl groups, or Rand Rmay together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; if Q is &#x2014;O&#x2014;, X is additionally selected from &#x2014;C(&#x2550;O)&#x2014;NRR, wherein Rand Rare independently selected from hydrogen, optionally substituted Calkyl, Caryl, or Cheterocyclyl groups, or Rand Rmay together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and if Q is &#x2014;NH&#x2014;C(&#x2550;O)&#x2014;, &#x2014;Y&#x2014;X may additionally be selected from Calkyl.

DNA-PK inhibitors

Compounds of formula I: wherein A, B and D are respectively selected from the group consisting of:

The invention relates to the use of compounds of formula (I) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, in the preparation of a medicament for inhibiting the activity of DNA-PK, wherein Rand Rare independently hydrogen, an optionally substituted Calkyl group, Cheterocyclyl group, or Caryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; X and Y are selected from CRand O, O and CR'and NR&#x2033;and N, where the unsaturation is in the appropriate place in the ring, and where one of Rand Ror R&#x2032;is an optionally substituted Cheteroaryl or Caryl group, and the other of Rand Ror R&#x2032;is H, or Rand Ror R&#x2033;together are &#x2014;A&#x2014;B&#x2014;, which collectively represent a fused optionally substituted aromatic ring. The compounds also selectively inhibit the activity of DNA-PK compared to PI 3-kinase and/or ATM.

The invention relates to trycyclic lactam indole derivatives and triacyclic lactam benzimodole derivatives and their use in inhibiting the activity of PARP enzyme. The invention also relates to the use of these compounds in the preparation of medicaments.

Therapeutic compounds

A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein:

The invention relates to the use of compounds of formula (I) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, in the preparation of a medicament for inhibiting the activity of DNA-PK, wherein Rand Rare independently hydrogen, an optionally substituted Calkyl group, Cheterocyclyl group, or Caryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; X and Y are selected from CRand O, O and CR'and NR&#x2033;and N, where the unsaturation is in the appropriate place in the ring, and where one of Rand Ror R&#x2032;is an optionally substituted Cheteroaryl or Caryl group, and the other of Rand Ror R&#x2032;is H, or Rand Ror R&#x2033;together are -A-B&#x2014;, which collectively represent a fused optionally substituted aromatic ring. The compounds also selectively inhibit the activity of DNA-PK compared to PI 3-kinase and/or ATM.

The present invention provides compounds of formula (I) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein Rand Rare independently hydrogen, an option ally substituted Calkyl group, Cheterocyclyl group, or Caryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and Ris an optionally substituted Cheterocyclyl or Caryl group, and their use as pharmaceuticals, particularly in treating diseases which are retroviral mediated or ameliorated by the inhibition of DNA-PK, 

Thiopyrane-4-ones as DNA protein kinase inhibitors

Growing community of inventors

Newcastle upon Tyne, United Kingdom

Nicola Curtin