Clinically Applicable Inhibitors Impacting Genome Stability

Abstract

Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases.

Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

“…Developed MOF inhibitor DC-M01-7 downregulates H4K16ac, inhibiting proliferation of human colon cancer (HCT116) cells ( 196 ). Furthermore, through the role of HATs in DNA damage repair, several novel HAT inhibitors sensitize cancer cells to the cytotoxic effects of radiation therapy, suggesting their potential as adjuvants in this context ( 197 , 198 ). However, there are few reports on selective inhibitors targeting members of this family.…”

Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer

“…Small molecules targeting centrosome components have been developed and tested in vitro and in vivo with some currently undergoing clinical trials [9]. The three main targets to centrosome control involve: (1) Centrosome duplication proteins (PLK1, CDK2, PLK4, AURKA), (2) centrosome amplification proteins (CHK1, PI3K, AKT, PLK4), and (3) centrosome clustering proteins (APC, HSP70, Stathmin) [9].…”

The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?

“…Regarding PLK inhibitors, a phase I trial with CFI-400945 is currently ongoing in relapsed/refractory AML and MDS (NCT03187288). CFI-400945 was initially developed to target PLK4 that regulates centrosome duplication and genome integrity and its inhibition showed promising results in preclinical studies of solid tumors [128]. Recently, a dual activity of the drug on both PLK4 and Aurora B has been suggested [129], which may provide an intrinsic synthetic lethal combination in selected models.…”