Checkpoint Kinase 1 (Chk1) is the Company’s most advanced programme. It was licensed to Sierra Oncology Inc. (NASDAQ: SRRA) in September 2016. Sierra are now responsible for progressing the candidate drug through clinical trails and to the market. The clinical development candidate drug, SRA737 (formerly PNT737 and CCT245737), and other lead series compounds have shown strong potency in disease models of:
Phase 1 clinical trials of CCT245737, commenced in Q2 2016, in collaboration with the Cancer Research Technology (CRT) Pioneer Fund. These trials will ultimately target bladder and pancreatic cancers in combination with standard-of-care chemotherapy, and prostate, ovarian, non-small cell lung, head & neck and colorectal cancers as a single agent. Both trials are taking place in hospitals in London, Cardiff and Newcastle, and the single agent trials are also being conducted in Oxford and Edinburgh. They are expected to complete in Q1 2019 (single agent) and Q2 2019 (chemotherapy combination).
Chk1 kinase acts as a key regulator of cell cycle checkpoints and central mediator of the DDR (DNA damage response) network. Chk1 regulates multiple cell-cycle phases, temporarily pausing cell replication and division allowing for DNA repair. Chk1 also directly activates several proteins involved in the repair of damaged DNA.
Malignant tumour cells tolerate substantially greater levels of genomic instability than would be acceptable in healthy cells. Despite accumulating considerable DNA damage due to replicative stress or defects in DNA repair machinery, cancer cells survive and replicate via an over-reliance on select components of the DDR network, including Chk1. Consistent with this observation, Chk1 inhibition has shown to be synthetically lethal to cancer cells harbouring functional genetic alterations in certain oncogenes (such as MYC, RAS, ATM, BRCA1, BRCA2 and TP53). This provides an opportunity to treat cancers with high replication stress and genomic instability, identified through biomarkers, with Chk1 inhibitor therapy.
Certain standard chemotherapeutic drugs (such as gemcitabine, cisplatin, docetaxel and topotecan) and radiotherapy also induce DNA damage to kill cancer cells. There is considerable preclinical evidence to support the synergy potential between combinations of these standard chemotherapies and Chk1 inhibitors.
Sareum/ICR Journal Medicinal Chemistry paper: "Multi-parameter lead optimization to give an oral checkpoint kinase 1 (CHK1) inhibitor clinical candidate: (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)" J. Med. Chem. 2016, 59(11), 5221-5237 Abstract
Sareum/ICR Oncotarget journal paper: "The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma" Oncotarget 2015, 7(3) 2329-2342 Abstract , Download PDF
Business Weekly "US deal hands Sareum share of potential $328M windfall" Link to online article 27 September 2016
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