Checkpoint Kinase 1 (Chk1) is Sareum's most advanced programme. It was discovered and advanced into first clinical trials in collaborations with the Institute of Cancer Research and the CRT Pioneer Fund. The clinical candidate drug, SRA737 (formerly CCT245737), and other lead series compounds have shown strong potency in numerous cancer models.
SRA737 is first-in-class, highly selective for Chk1 and is administered orally, giving it a competitive advantage over previous leading clinical-stage competitors.
SRA737 has now completed two Phase 1/2 clinical trials in genetically selected patients with advanced cancers, conducted by former licence partner, Sierra Oncology:
a monotherapy study evaluating SRA737 in patients with tumours identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition, including ovarian, prostate, non-small cell lung, head & neck and anus, and colorectal cancers; and
a drug combination study evaluating SRA737 potentiated by low-dose gemcitabine (LDG) in four cancer indications, including ovarian, small cell lung, sarcoma, and cervical/anogenital
The monotherapy trial completed in October 2019 with 112 patients enrolled. The LDG combination trial completed in April 2020 with patients 153 enrolled. These trials took place in hospitals throughout the UK and Europe.
Sierra presented positive preliminary safety & efficacy data from SRA737+LDG combination trail at ASCO in June 2019, which potentially supports further development in anogenital cancer
In addition, Sierra Oncology and their collaborators have published encouraging preclinical data demonstrating the synergy of SRA737 or SRA737+LDG in combinations with immune checkpoint, PARP and DNA polymerase inhibitors.
How it works
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, CCNE1 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.
Cancer Research UK CRUK/16/005
Cancer Research UK CRUK/16/002
Phase 1/2 Trial results: "A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer". R Jones R Plummer, V Moreno, L Carter, D Roda, E Garralda, R Kristeleit, D Sarker, T Arkenau, P Roxburgh, HS Walter, S Blagden, A Anthoney, BJ Klencke, MM Kowalski & U Banerji, Clin Cancer Res, 15 November 2022.
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
News Release: Licence agreement for Chk1 inhibitor CCT245737
News Release: CHK1 Approved for Clinical Trials
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