Cancer cells are notoriously resilient, developing various mechanisms to evade the cytotoxic effects of chemotherapy. One such mechanism involves the checkpoint kinase 1 (CHK1) protein, a key regulator of the DNA damage response (DDR). When DNA damage occurs, CHK1 halts the cell cycle, providing time for DNA repair. However, in cancer cells with inherent DNA damage due to rapid growth or mutated oncogenes, CHK1 activation allows them to survive and proliferate despite chemotherapy-induced DNA damage[4]. Recognizing this vulnerability, scientists at The Institute of Cancer Research, London, developed CCT245737, a potent and selective CHK1 inhibitor, now also known as SRA737, with the potential to overcome chemotherapy resistance [1, 6].
The Role of CHK1 in Cancer Cell Survival
CHK1 is a serine/threonine kinase that plays a crucial role in maintaining genomic stability and regulating cell cycle progression[1]. It is activated in response to DNA damage, replication stress, and mitotic errors[1]. Once activated, CHK1 phosphorylates various downstream targets, leading to cell cycle arrest, DNA repair, and ultimately, cell survival[1]. By blocking CHK1, cancer cells with intrinsic DNA damage due to rapid growth or mutated oncogenes may be vulnerable to synthetic lethality, leading to cell death[4][5].
CCT245737: A Potent and Selective CHK1 Inhibitor
CCT245737 is an orally bioavailable, small-molecule inhibitor of CHK1 discovered at the Cancer Therapeutics Unit, Institute of Cancer Research [1, 6]. Preclinical studies have demonstrated that CCT245737 is a potent and selective inhibitor of CHK1, with an IC50 of 1.4 nM against the CHK1 enzyme and >1,000-fold selectivity against CHK2 and CDK1[1][2]. In vitro kinase profiling showed that CCT245737 (10 μM) inhibited only 12 out of 124 kinases by >80%, confirming its selectivity for CHK1[2].
Mechanism of Action
CCT245737 inhibits CHK1 activity, preventing the DNA damage-induced cell cycle arrest and forcing cancer cells to divide with damaged DNA [2, 5]. This leads to increased DNA damage, genomic instability, and ultimately, apoptosis (programmed cell death) [1, 2]. In essence, CCT245737 deprives cancer cells of their ability to repair DNA damage, making them more vulnerable to chemotherapy [1, 5].
Preclinical Studies: Promising Results
Preclinical studies have shown that CCT245737 enhances the cytotoxicity of various chemotherapeutic agents, such as gemcitabine and SN38, in multiple human tumor cell lines and human tumor xenograft models [1, 2]. Notably, CCT245737 enhanced gemcitabine antitumor activity to a greater degree than higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination [1, 2]. Furthermore, CCT245737 exhibited significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma[1].
An in vivo pharmacokinetic-pharmacodynamic (PK-PD) study in HT29 tumor xenografts demonstrated that CCT245737 inhibited CHK1 activity and abrogated gemcitabine-induced cell cycle arrest, causing DNA damage and cell death[2]. In addition, CCT245737, in combination with LY188011, inhibited tumor growth in HT29 colon cancer xenografts[7].
Clinical Development and Ongoing Trials
Given its promising preclinical profile, CCT245737 (SRA737) has entered clinical development. It is being evaluated in Phase 1 and Phase 2 clinical trials for various cancers [1, 5]. A Phase 1/2 trial of SRA737 in combination with chemotherapy is ongoing to determine its safety, tolerability, and efficacy in patients with advanced solid tumors. Further research in prostate cancer also indicates the CHK1 inhibitor SRA737 are in clinical trials for various cancers[8].
Challenges and Future Directions
While CCT245737 (SRA737) holds great promise as a chemosensitizing agent, several challenges remain:
- Patient Selection: Identifying the patients most likely to benefit from CCT245737 (SRA737) is crucial. Predictive biomarkers are needed to select patients whose tumors are dependent on CHK1 for survival.
- Combination Strategies: Determining the optimal combination of CCT245737 (SRA737) with chemotherapy or other targeted therapies is essential to maximize efficacy and minimize toxicity.
- Resistance Mechanisms: Understanding potential mechanisms of resistance to CCT245737 (SRA737) is important for developing strategies to overcome resistance.
CCT245737 (SRA737) represents a promising new approach to cancer therapy, aiming to overcome chemotherapy resistance by targeting CHK1, a key regulator of the DNA damage response [1, 5]. As clinical trials progress, it is hoped that CCT245737 (SRA737) will improve outcomes for patients with cancer.
Citations:
[1] https://pubmed.ncbi.nlm.nih.gov/26295308/
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC4823038/
[3] https://www.cancer.gov/publications/dictionaries/cancer-drug/def/chk1-inhibitor-sra737
[4] https://www.nature.com/articles/s41416-023-02279-x
[5] https://ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.TPS2607
[6] https://www.tandfonline.com/doi/full/10.4155/bio-2017-0043
[7] https://www.medchemexpress.com/CCT245737.html
[8] https://synapse.patsnap.com/drug/32bdb04583b043818d7808672c8fa1c6
