Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties

  • J Med Chem. 2015 Oct 22;58(20):8309-13. doi: 10.1021/acs.jmedchem.5b01242.
Mark D Charles  1 ,  Joanna L Brookfield  1 ,  Tennyson C Ekwuru  1 ,  Martin Stockley  1 ,  John Dunn  1 ,  Michelle Riddick  1 ,  Tim Hammonds  2 ,  Elisabeth Trivier  2 ,  Gavin Greenland  2 ,  Ai Ching Wong  2 ,  Anne Cheasty  1 ,  Susan Boyd  3 ,  Diane Crighton  4 ,  Michael F Olson  4
Affiliations
  • 1. Cancer Research Technology Discovery Laboratories , Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
  • 2. Cancer Research Technology Discovery Laboratories, London Bioscience Innovation Centre , Royal College Street, London NW1 0NH, U.K.
  • 3. CompChem Solutions Ltd, St John's Innovation Centre , Cambridge CB4 0WS, U.K.
  • 4. Beatson Institute, Cancer Research U.K. , Garscube Estate, Switchback Road, Glasgow G61 1BD, U.K.
PMID: 26356364 DOI: 10.1021/acs.jmedchem.5b01242
Abstract

As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.

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