DDR1 Selective Inhibitors for the Treatment of Lung Cancer
Compound 7rh is from a new class of DDR1 selective inhibitors that could fulfill an unmet medical need in non-small cell lung cancer (NSCLC).
Indication and Market
Dysregulation of DDR1 and DDR2 has been linked to a number of human diseases, including fibrotic disorders, atherosclerosis, and various cancers. For instance, overexpression of DDR1 is associated with the poor prognosis in non-small cell lung cancer and is implicated in cell survival and invasiveness in hepatocellular carcinoma, pituitary adenoma and prostate cancer. High expression levels and/or mutation of DDRs are frequently detected in cancer cell lines and primary tumor tissues from lung, breast, brain, ovary, head and neck, liver, pancreas and prostate.
Compound 7rh inhibits the enzymatic activity of DDR1 with an IC50 value of 6.8 nM, but is significantly less potent in suppressing other kinase activities including DDR2, Bcr-Abl, and c-Kit. 7rh binds with DDR1 with a Kd value of 0.6 nM, while displaying low affinity for 455 other kinases tested. Ex vivo, 7rh blocks the proliferation of cancer cells that express high levels of DDR1 and strongly suppress cancer cell invasion, adhesion, and tumorigenicity. Preclinical pharmacokinetic studies show that 7rh possesses a good PK profile with oral bioavailability of 67.4%. The compound has a high degree of aqueous solubility, which affords the potential for parenteral formulation.
GIBH has filed intellectual property rights for composition of matter, production and medical use of compound 7rh for the treatment of NSCLC as well as various other cancers. Application patent number is 201310042505.X.
7rh is a low molecular weight, water soluble, containing 3‑(2-(Pyrazolo[1,5‑a]pyrimidin-6-yl)-ethynyl)benzamide pharmacophore.
Secondary: Breast and brain Cancer.
Compound 7rh, is being formulated as a tablet suitable for oral dosing.
Lead optimization: Preclinical proof-of-concept in several in vitro models of TTP. In vivo efficacy studies are ongoing in two rodent models of TTP. Candidate selection of the drug is scheduled for late 2014 and IND filing is to be initiated in 2016.
Candidate selection of the drug is scheduled for late 2014 and IND filing is to be initiated in 2015 for NSCLC.