1131802-75-9Relevant academic research and scientific papers
Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d] pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization
Davies, Nicholas G.M.,Browne, Helen,Davis, Ben,Drysdale, Martin J.,Foloppe, Nicolas,Geoffrey, Stephanie,Gibbons, Ben,Hart, Terance,Hubbard, Roderick,Jensen, Michael Rugaard,Mansell, Howard,Massey, Andrew,Matassova, Natalia,Moore, Jonathan D.,Murray, James,Pratt, Robert,Ray, Stuart,Robertson, Alan,Roughley, Stephen D.,Schoepfer, Joseph,Scriven, Kirsten,Simmonite, Heather,Stokes, Stephen,Surgenor, Allan,Webb, Paul,Wood, Mike,Wright, Lisa,Brough, Paul
, p. 6770 - 6789 (2013/01/15)
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d] pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
PYRROLOPYRIMIDINE DERIVATIVES HAVING HSP90 INHIBITORY ACTIVITY
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Page/Page column 37-38, (2009/04/25)
Compounds of formula (I) are inhibitors of HSP90, and are useful inter alia in the treatment of cancers, wherein R is cyano or methoxy; R1 and R2 are independently selected from hydrogen, optionally substituted C1-C3 alkyl, and optionally substituted C3-C6 cycloalkyl; or R1 and R2 taken together with the nitrogen to which they are attached form a 3- to 7-membered ring optionally substituted by chloro, bromo, cyano, C1-C3 alkyl in which one or more hydrogens are optionally replaced by fluorine, or hydroxy(C1-C3 alkyl)- in which one or more hydrogens in the alkyl part are optionally replaced by fluorine; R3 and R4 are independently selected from hydrogen, C1-C3 alkyl in which one or more hydrogens are optionally replaced by fluorine, and cyclopropyl; or R2 and R3 taken together with the carbon to which they are attached form a 3- to 6-membered ring cycloalkyl ring; n is 1, 2 or 3; and Z is (i) -NR5R6 wherein R5 and R6 are independently selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl; or R5 and R6 taken together with the nitrogen to which they are attached form a 3- to 7-membered ring optionally substituted by chloro, bromo, cyano, C1-C3 alkyl in which one or more hydrogens are optionally replaced by fluorine, or hydroxy(C1-C3 alkyl)- in which one or more hydrogens in the alkyl part are optionally replaced by fluorine; or (ii) C1-C3 alkoxy in which one or more hydrogens in the alkyl part are optionally replaced by fluorine.
