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  • PD-1/PD-L1 Inhibitor 3 br Concluding remark br Acknowledgeme

    2020-02-14


    Concluding remark
    Acknowledgements
    Detection and repair of the numerous, and potentially lethal, DNA lesions arising in human PD-1/PD-L1 Inhibitor 3 daily is largely mediated by an efficient system collectively termed the DNA-damage response (DDR). Paradoxically, DNA-repair processes within cancer cells also constitute a mechanism of resistance to DNA-damaging anticancer therapies, and agents that impede DNA repair are thus of potential therapeutic interest as chemo- and radio-sensitising agents in the treatment of cancer., Perhaps more interestingly, DDR defects are a common feature of cancer and the ‘mutator-phenotype’ associated with the resultant genomic instability may offer a survival advantage over normal tissues, albeit that tumour dependency on a remaining DNA-repair pathway can result. This offers the exciting opportunity of achieving tumour selectivity through pharmacological inhibition of an essential DNA repair pathway, as elegantly demonstrated recently by the synthetic lethality achieved with poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors in BRCA1 and BRCA2 deficient tumours (reviewed in Refs. and ). The phosphatidylinositol-3-kinase related kinase (PIKK) family member DNA-dependent protein kinase (DNA-PK) plays a key role in the DDR, via the non-homologous end-joining pathway of DNA double-strand break (DSB) repair. Importantly, inhibition of this kinase has been demonstrated to potentiate the cytotoxicity of DNA DSB-inducing anticancer therapies, and there is evidence that DNA-PK is over-expressed in a number of tumours. The development of clinically useful ATP-competitive DNA-PK inhibitors is a major goal of our research. In the absence of suitable structural information for DNA-PK, we have conducted structure-activity relationship (SAR) studies around the 2-morpholino-4-chromen-4-one pharmacophore () from which the non-selective PIKK inhibitor LY294002 () was derived. These studies resulted in the identification of a number of interesting DNA-PK inhibitors, including the thiophen-2-yl () and 8-biphenyl derivatives (), as well as NU7441 (; IC=30nM),, elaboration of which has led to the highly potent water-soluble DNA-PK inhibitor KU-0060648 (; IC=5nM). Importantly, preclinical proof-of-principle studies with and have demonstrated activity in vitro as chemo- and radio-potentiators in a range of human tumour cell lines, and initial in vivo investigations with these agents have been promising., With a view to identifying new DNA-PK inhibitors, we have investigated alternative heterocyclic scaffolds, and have previously demonstrated that sub-micromolar DNA-PK inhibitory activity also resides in suitably substituted pyran-2-ones () and pyran-4-ones ()., These studies imply that the ring oxygen of chromenone- and pyranone-based DNA-PK inhibitors does not contribute directly to inhibitor binding. By contrast, the morpholin-4-yl and carbonyl oxygen functions are thought to make key hydrogen bond interactions within the ATP-binding domain, with the pendant aryl substituent occupying a putative hydrophobic pocket. This ‘3-point binding’ interaction is thought to determine the overall orientation and positioning of the inhibitor. Accordingly, a superimposition of the chromenone of with the isomeric coumarin and isocoumarin heterocyclic systems provided an opportunity to investigate a scaffold-hopping strategy, through the introduction of aryl substituents at the coumarin 6- or 7-positions and the isocoumarin 5-position (). This was supported by a previous observation that 6-methoxycoumarin () is approximately equipotent with the isomeric 8-methoxychromenone ( (DNA-PK, IC values of 1.8μM and 1.2μM, respectively). Given the high potency of and , it was also of interest to examine the impact on activity of the subtle structural changes imposed by moving the ring oxygen atoms.
    Introduction Programmed cell death (PCD) or apoptosis is a normal process by which unwanted cells in multicellular organisms are eliminated during embryonic development and in adult life [1], [2]. Apoptosis also plays a major role in counteracting tumor growth and, therefore, acquired defects in apoptotic signaling pathways are one of the hallmarks of cancer [3], [4]. During PCD, a specific family of cysteine proteases, the caspases, are activated and proteolyse a large number of substrates resulting in the destruction of the apoptotic cell [5]. The morphological changes triggered by caspases include shrinkage of the cell, chromatin condensation, DNA fragmentation, and the eventual disintegration of the cell into small fragments that can be engulfed by neighboring cells. There are two major pathways leading to caspase activation during apoptosis: the extrinsic or death receptor pathway [6] and the intrinsic or mitochondrial pathway [7]. Most anticancer drugs activate the intrinsic apoptotic pathway [8]. One such PD-1/PD-L1 Inhibitor 3 example of a potent inducer of PCD is the alkaloid staurosporine, derivatives of which are currently undergoing clinical trials as chemotherapeutic agents [9], [10], [11].