Cancer – Chk1 kinase

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:

lung, pancreatic and colon cancers in combination with chemotherapy
Acute Myeloid Leukaemia (AML), B-cell lymphoma, breast cancer and paediatric neuroblastoma as a single agent
head and neck cancers in combination with radiotherapy

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).

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 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

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