United Kingdom Research and Innovation

Inflectis Bioscience

Other

Medical Research Council

Centre National De La Recherche Scientifique

Ecole Normale Superieure

Anne Bertolotti

Philippe Guedat

Agnieszka Krzyzosiak

Kim Schneider

Anna Gudny Sigurdardottir

Indrajit Das

Adrien Rousseau

Marc Blondel

The present invention discloses a method to discover selective inhibitors of phosphatases. Thus the invention provides a method for screening a test compound to determine whether the compound binds a holophosphatase selectively or non-selectively comprising: i) providing a first holophosphatase wherein said holophosphatase is captured/immobilised; ii) testing a test compound for its ability to bind to the first holophosphatase; iii) providing a second holophosphatase wherein said second holophosphatase is captured/immobilised; iv) testing the same test compound for its ability to bind to the second holophosphatase; v) comparing the binding of the test compound to said first holophosphatase with the binding to said second phosphatase wherein a compound that binds a holophosphatase selectively will bind to said first holophosphatase but not said second holophosphatase; or will bind to said second holophosphatase but not said first; or wherein a compound that binds a holophosphatase non-selectively will bind to both said first holophosphatase and said second holophosphatase.

Methods for selecting phosphatase selective and non-selective phosphatase inhibitors

The present invention relates to inhibitors of PPP1 R15A and PPP1 R15B and their use in therapy, particularly in the treatment of a disease state alleviated by the inhibition of PPP1 R15A and PPP1 R15B, for example a disorder associated with accumulation of misfolded proteins or proteostatsis disorder. Compounds of the invention include compounds having the formula IA or a pharmaceutically acceptable salt thereof, wherein R, R, R, Xand Yare as defined herein. 

Inhibitors and their uses

The present invention relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein: Ris alkyl, Cl, F or Br; Ris H or F; Ris selected from H and alkyl; Ris selected from H and C(O)R; Ris H; or Rand Rare linked to form a heterocyclic group which is optionally substituted with one or more Rgroups; Ris selected from R, ORand NRR; R, Rand Rare each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl and aryl, each of which is optionally substituted with one or more Rgroups; each Ris independently selected from halogen, OH, CN, NO, COO-alkyl, aralkyl, SO-alkyl, SO-aryl, COOH, CO-alkyl, CO-aryl, NH, NH-alkyl, N(alkyl), CF, alkyl and alkoxy; X and Z are each independently CR, and Y is selected from CRand N; and Ris H or F; for use in treating a disorder associated with protein misfolding stress and in particular associated with accumulation of misfolded proteins.

Benzylideneguanidine derivatives and therapeutic use for the treatment of protein misfolding diseases

The present invention relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein Ris alkyl, Cl, F or Br, Ris H or F; Ris selected from H and alkyl; Ris selected from H and C(O)R; Ris H or Rand Rare linked to form a heterocyclic group which is optionally substituted with one or more Rgroups Ris selected from R, ORand NRR; RRand Rare each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocycyl and aryl, each of which is optionally substituted with one or more Rgroups; each Ris independently selected from halogen, OH, CN NO, COO-alkyl, aralkyl, SO-alkyl, SO-aryl, COOH, CO-alkyl, CO-aryl, NH, NH-alkyl, N(alkyl), CF, alkyl and alkoxy, X and Z are each independently CRand Y is selected from CRand N and Ris H or F; for use in treating a disorder associated with protein misfolding stress and in particular associated with accumulation of misfolded proteins. 

The present invention relates to a compound of formula (I), or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein: Ris alkyl, Cl, F or Br; Ris H or F; Ris selected from H and alkyl; Ris selected from H and C(O)R; Ris H; or Rand Rare linked to form a heterocyclic group which is optionally substituted with one or more Rgroups; Ris selected from R, ORand NRR; R, Rand Rare each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl and aryl, each of which is optionally substituted with one or more Rgroups; each Ris independently selected from halogen, OH, CN, NO, COO-alkyl, aralkyl, SO-alkyl, SO-aryl, COOH, CO-alkyl, CO-aryl, NH, NH-alkyl, N(alkyl), CF, alkyl and alkoxy; X and Z are each independently CR, and Y is selected from CRand N; and Ris H or F; for use in treating a disorder associated with protein misfolding stress and in particular associated with accumulation of misfolded proteins. 

The invention relates to chlorine Guanabenz derivatives for treating Huntington's disease and other polyglutamine expansion associated diseases. More specifically, it relates to the use of the molecule of formula (I) wherein R&#x2550;H or Cl and the phenyl group is at least substituted twice, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating polyglutamine expansion associated diseases. 

Growing community of inventors

Cambridge, United Kingdom

Anne Bertolotti