Tools for fragment based drug discovery

EPHA4

<BromodomainsMDM4 >

EPHA4


The EPHA4 receptor regulates the downstream kinase Jak2 and the transcription activator Stat3 which are involved in cell growth and viability.1 EPHA4 was found to be highly overexpressed in tumor cells of cutaneous T-cell lymphomas (CTCL).2 Downregulation of EPHA4 with siRNA, in EPHA4 overexpressing prostate and pancreatic cancer cell lines, resulted in reduced cell viability and indicates the potential oncogenic properties of EPHA4.3,4 Furthermore, it has been suggested that EPHA4 plays a role in gastric cancer via the EPHA4/FGFR1 hetero-receptor mediated FGFR downstream signaling.5 These results suggest that EPHA4 might be a promising target for pharmacologic intervention in oncology.

In addition to oncology indications, it has been suggested that EPHA4 inhibition might be beneficial for the treatment of spinal cord injuries due to its inhibitory effect on axon extension.6,7 EPHA4 was also identified as a modifier of the disease phenotype in amyotrophic lateral sclerosis (ALS) models where its inhibition might be beneficial for the treatment of ALS.8

epha4-2

Hits from the ZoBio library have been identified using TINS and validated using SPR. The crystal structure of apo-EphA4 has been solved and successful soaking studies have been performed. One hit series has been elaborated to single digit µM potency and evaluated for specificity vs a panel of kinases.9 All resources are in place to begin immediate structure-based hit-to-lead studies.

 

References:

  1. Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle – Implications in the regulation of acetylcholinesterase expression. Lai, J. Biol. Chem., 2004.
  2. Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sezary syndrome identified by gene expression analysis. Van Doorn, Cancer Res., 2004.
  3. Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs. Ashida, Cancer Res., 2004.
  4. EphA4 receptor, overexpressed in pancreatic ductal adenocarcinoma, promotes cancer cell growth. Iiizumi, Cancer Sci., 2006.
  5. Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. Oki, World J. Gastroenterol., 2008.
  6. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Fabes, Eur. J. Neurosci., 2007.
  7. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. Goldshmit, J. Neurosci., 2004.
  8. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Van Hoecke, Nat. Med., 2012.
  9. Fragment based lead discovery of small molecule inhibitors for the EPHA4 receptor tyrosine kinase. Van Linden, Eur. J. Med. Chem., 2012.

<BromodomainsMDM4 >