Novel and selective inhibitors of SRC family kinases
Novel compounds displaying high potency and selectivity toward SRC family kinases have been developed. The lead compound eCF506 displays subnanomolar potency against SRC, high selectivity over ABL kinase (>1000-fold), optimal pharmacokinetic profile and in vivo target engagement.
- Oncology: combination therapies in advanced cancer disease
- Diabetic eye disease
- Neurodegenerative diseases
(WO 2016/185160 A1)
- Collaborative research
SRC is a non-receptor tyrosine kinase, which is overexpressed and/or over-activated in many types of cancer. SRC has been shown to have a crucial role in many aspects of tumour growth and development, including proliferation, migration, invasion, angiogenesis, metastasis and resistance to chemotherapy. Increased expression and activity of SRC correlate with advanced malignancy and poor clinical prognosis. All current SRC inhibitors display potent activity against Abl1, which results in undesired side effects (such as cardiotoxicity) and lower anti-cancer activity in certain tumour types.
Novel compounds displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner.
The preclinical candidate eCF506 inhibits SRC kinase at subnanomolar levels with very high selectivity over ABL (>1000-fold). The compound displays excellent drug-like physiochemical properties, and is orally bioavailable with excellent efficacy in cells (EC50 below 10 nM) and in vivo pharmacokinetic profile. Inhibition of SRC phosphorylation and downstream signaling (FAK, paxillin) following oral, iv and IP administration has been demonstrated in breast and colorectal cancer xenograft models.
Proof of concept experiments have been conducted in vitro and in vivo, in zebrafish and xenograft models of breast and colorectal cancer.
- High anti-proliferative and anti-invasive activity in various cancer cell lines
- Improved Safety: no ABL inhibition liability, which is associated with cardiotoxicity
- Good oral bioavailability, half-life, stability
Fraser et al. J. Med. Chem. 2016, 59, 4697−4710