CDK Inhibitors in Leukemia and Lymphoma
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
UCN-01 (7-hydroxystaurosporine, NSC638850 or KW-2401; Kyowa Hakka Kogyo Company Ltd., Tokyo, Japan), a derivative of the nonspecific PKC inhibitor staurosporine (a natural product isolated from Streptomyces staurosporeus), was originally developed as a selective PKC inhibitor. Studies have also reported that UCN-01 inhibits several CDKs. However, recent studies have shown that it exerts other antitumor effects, including inhibition of Chk1, which results in “inappropriate” activation of CDKs and abrogation of DNA damage-induced cell cycle checkpoints, as well as interference with the PDKl/Akt survival pathway, thus promoting induction of apoptosis. These effects are largely independent of PKC inhibition. UCN-01 displays antitumor activity in in vitro systems and in vivo xenograft models involving multiple human tumor types, with greater antitumor effects observed in longer administration intervals (e.g., 72 hours in in vitro systems) (23).
Biologically Targeted Agents in Head and Neck Cancers
John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford in Head & Neck Surgery Plastic Surgery, 2018
Chk1 is directly downstream of ATR in the DNA damage response signalling cascade and is phosphorylated by it. A number of Chk1 inhibitors have been tested preclinically,70 but few have entered clinical trials. UCN-01 showed enhancement of radiation and genotoxic chemotherapy-induced cytotoxicity that was selective for p53-dysfunctional cells.71 It was tested in phase I trials as monotherapy72 and in combination with DNA-damaging agents such as platinum,73 topoisomerase inhibitors74 and nucleoside analogues.75, 76 In phase II studies, UCN-01 was tested combined with DNA-damaging chemotherapy but its development was aborted due to lack of clinical efficacy.77–79
Irradiation-induced damage and the DNA damage response
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
The third kinase that quickly responds to DNA damage and is capable of phosphorylating H2AX is ATR. In contrast to ATM and DNA-PKcs, ATR does not appear to play any substantial role in signalling initiated by radiation-induced DSBs. Instead, it phosphorylates H2AX in response to other types of DNA damage and abnormalities such as single-stranded DNA and stalled or broken replication forks. ATR is thus very important for the types of damage that occur during normal DNA replication. Single-stranded DNA regions coated with RPA recruit the mediator protein ATRIP (ATR interacting protein) and ATR. Although ATR is less important in the initial processing of radiation-induced DSBs, it does play a role in this pathway after ATM is activated. Activation of the ATM-MRN complex leads to processing of the DNA at sites of DSB. This processing can create stretches of single-stranded DNA through extensive DSB end resection, which will then activate ATR. Thus, ATR can be activated ‘downstream’ of ATM activation. ATR is also activated as a consequence of replication problems following irradiation. DNA strand cross links and oxidized bases caused by radiation interfere with replication and activate ATR (20). ATR shares some of the phosphorylation targets of ATM but also phosphorylates a distinct set of proteins that participate in the DDR. Consequently, components of the DDR effector pathways (DNA repair, checkpoints and cell death) are also dependent on ATR after radiation treatment. For example, the ATR kinase phosphorylates crucial checkpoint proteins such as CHK1, thereby providing a strong link to cell-cycle regulation.
Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Ivana Malvacio, Alberto Cuzzolin, Mattia Sturlese, D. Mariano A. Vera, E. Laura Moyano, Stefano Moro
During the last decade, heterocycles sharing a common pattern with the previously studied pyrazoloquinolones have emerged as checkpoint kinase 1 (Chk1) inhibitors9–11. The serine-threonine protein kinase Chk1 is a key mediator in response to DNA damage which, along with the tumour suppressor protein p53, is required for cell cycle arrest and activation of DNA repair before progressing into mitosis. However, many tumour cells rely only on Chk1 checkpoint because of mutations in p53. Therefore, the inhibition of Chk1 represents a strategy to increase the therapeutic efficacy of anticancer drugs by enhancing the apoptosis in tumour cells with a defective p53 response12–15. The first Chk1 inhibitor to enter phase I and II clinical trials against a wide range of tumour types was UCN-01 (7-hydroxystaurosporine)16,17. Many Chk1 inhibitors have subsequently been developed and subjected to phase I trials like AZD776218, PF-47773619 and SCH90077620,21. Unfortunately, many of these clinical studies have been abandoned due to the low selectivity and the incidence of side effects of such compounds15,22.
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
CHK1 is a key protein kinase in the ATR DNA damage signaling pathway at the S and G2-M checkpoints. The CHK2 kinase is located downstream in the ATM pathway and is mediated through p53 [59]. Because functional p53 is required for DNA repair through the ATM/CHK2 pathway, tumors with TP53 mutations have an increased reliance on CHK1 in the presence of DNA damage as ATM/CHK2 signaling is defective [59]. BRCA plays a role in homologous recombination in response to replication stress, so it would be expected that efficacy of CHK1 inhibition would be greater in BRCA mutant tumors due to higher levels of replication stress [60,61]. Prexasertib currently has the most clinical experience of the CHK1 inhibitors. Interestingly, much of the success of prexasertib has been in BRCA wildtype tumors. In a phase II trial in high grade serous ovarian cancer, prexasertib monotherapy had a relative response rate of 11% in patients with BRCA mutated tumors however, the relative response in patients with BRCA wild-type tumors was 33% [61–63]. Additionally, in a phase II study in nine patients with BRCA wild-type triple negative breast cancer, the overall response rate with single-agent prexasertib was 11% with 4 additional patients achieving stable disease [64].
Disposition of [14C]LY2606368 following intravenous administration in patients with advanced and/or metastatic solid tumours
Published in Xenobiotica, 2020
Enaksha R. Wickremsinhe, Scott M. Hynes, Christopher D. Payne, Yingying Guo, Kenneth C. Cassidy
LY2606368 (prexasertib) is a potent and selective adenosine triphosphate-competitive inhibitor of checkpoint kinase 1 (CHK1). CHK1 is a multifunctional protein kinase and regulator of cell cycle progression (Dai & Grant, 2010). In response to exogenous DNA damage, CHK1 mediates cell cycle arrest to allow time for DNA repair or if the damage is extensive, to trigger apoptosis. CHK1 affects the initiation of DNA replication origin firing, stabilisation of replication forks, resolution of replication stress, and coordination of mitosis, even in the absence of exogenous DNA damage (Mcneely et al., 2014). Thus, the inhibition of CHK1 by compounds such as prexasertib disrupts DNA replication, induces DNA damage, and subsequently prevents repair, leading eventually to death by mitotic catastrophe due to the presence of unresolved DNA breaks (King et al., 2015). Prexasertib has also exhibited an acceptable safety profile in both nonclinical toxicology studies (with monitorable and reversible effects), and a phase 1 clinical study when administered at the recommended phase 2 dose (RP2D) of 105 mg/m2 as a 1-h infusion to patients with advanced cancer (Hong et al., 2016, 2018; Lee et al., 2018).
Related Knowledge Centers
- Ataxia Telangiectasia & Rad3 Related
- DNA Repair
- Synaptonemal Complex
- Oocyte
- Meiosis
- Serine/Threonine-Specific Protein Kinase
- Gene
- Testicle
- Atm Serine/Threonine Kinase
- Ataxia Telangiectasia & Rad3 Related
- Genetic Recombination