Cancer – Chk1 kinase

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, then licensed to Sierra Oncology Inc. (NASDAQ: SRRA) in September 2016. Sierra is now responsible for progressing the candidate drug through clinical trials and to the market. The clinical candidate drug, SRA737 (formerly CCT245737), and other lead series compounds have shown strong potency in numerous cancer models.

SRA787 is highly selective for Chk1 and is administered orally, giving it a competitive advantage over the leading clinical-stage competitor.

SRA737 is now being investigated in two Phase 2 clinical trials in patients with advanced cancer, with a primary focus on ovarian cancer:

• 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 in four cancer indications, including ovarian, small cell lung, sarcoma, and cervical/anogenital

The monotherapy trial is in the efficacy-oriented Phase 2 stage of the study, with 145 patients expected to be enrolled. The low-dose gemcitabine combination trial entered the Phase 2 stage in Q2 2018 has a terget enrollment of 80 patients. These trials are taking place in hospitals throughout the UK and Europe. Preliminary Phase 2 data is expected to be reported at a medical conference in H1 2019.

In addition, Sierra Oncology is planning to initiate a Phase 1b/2 combination trial of SRA737 with the orally administered PARP inhibitor, niraparib, in patients with prostate cancer in H1 2019.

Sierra has also presented preclinical data providing evidence of synergy between SRA737 and immune checkpoint blockade, and is currently designing a clinical study for this combination.

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.

Related Items

Sierra Oncology website

SRA737

DNA Damage Response

SRA737 / PNT737 / CCT245737 Clinical Trials Information

Chemotherapy Combination Study

ClinicalTrials.gov NCT02797977

NHS Clinical Trials Gateway #35675

Cancer Research UK CRUK/16/005

Single Agent Study

ClinicalTrials.gov NCT02797964

NHS Clinical Trials Gateway #35692

Cancer Research UK CRUK/16/002

Journal Articles

Sierra Oncology poster presentations http://investor.sierraoncology.com/publications

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

News

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

Cambridge News: Sareum Helps Develop "Chemotherapy Booster"