Inhibitors of LIMK1 and LIMK2
Development Stage: 3 - Hit to Lead
Description
Hit-to-Lead/Lead Optimisation - CTx/CRT Discovery Laboratories Project
CRT are seeking a commercial partner to undertake further in vitro and in vivo development of an exciting collection of potent pre-clinical LIMK1/2 inhibitors, with potential application in cancer and ocular disease. In particular, validation data suggests LIMK inhibitors may be effective in breast and prostate cancer indications, as well as ocular hypertension/glaucoma. Two potent chemical series are subject to recent priority patent filings.
Therapeutics Rationale
LIMK1/2 are ser/thr kinases which are upregulated in metastatic breast and prostate tumours. Overexpression of LIMK has been demonstrated to increase tumour cell migration and invasion and to increase tumour growth, angiogenesis and metastasis in vivo. Conversely, abrogation of LIMK function results in decreased breast cancer cell motility and formation of osteolytic bone lesions in an animal model of invasion.
By virtue of their role as effectors of Rho and cdc42 pathways involving ROCK, PAK1, PAK4 and MRCK, the LIM kinases are implicated as key regulators of the cytoskeleton. Several reports have also suggested cross-talk between LIMK and the TGF-b superfamily, key mediators of fibrotic responses. Downregulation of LIMK1 has been demonstrated to reduce inflammation in a mouse model of ocular surgery.
Furthermore, small molecule inhibition or genetic deletion of LIMK2 is effective in reducing intraocular pressure in mouse models, a key risk factor in disease progression in glaucoma.
For more information please contact
Dr Tanya Moore
+44 (0) 20 3469 6300 .(JavaScript must be enabled to view this email address)