DDR Compounds in Development

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Compounds other than PARP1/2 inhibitors targeting DDR network molecules are in various stages of development (see the examples in the table below), primarily in settings of either HRD cancers, or in combination with chemotherapies and other targeted agents [1-4]. The efficacy of single agents targeting DDR will depend on selecting patients with genetic backgrounds for DDR dependency [5].

Table 6: Examples of compounds targeting DDR (other than PARP1/2 inhibitors) in clinical development (as of May 2019)

Some current examples of combination therapies being explored include targeting multiple DDR pathways (e.g. ATR in ATM-deficient tumours, targeting WEE1 in cyclin E or MYC amplified tumours, and using POLQ inhibitors in HRD or NHEJ deficient tumours) and combining a DDR-targeting agent with chemotherapy (e.g. combining CHK1/2 and WEE1 inhibitors with chemotherapy to abrogate the G2/M checkpoint) [5]. As expected, efficacy as part of combination therapy will depend on identifying the timing and dosing regimen with the combination partner, limiting toxicities and maintaining a beneficial therapeutic index [5].

In the preclinical setting there are a number of promising DDR targets that are being investigated [5]. These include PARG, RAD51 and further studies of POLQ. Small molecule inhibitors of PARG have been developed, which have allowed a more thorough investigation of how PARG functions intracellularly, opening up the potential to target it in the future [6, 7]. Likewise, a small molecule inactivator of RAD51 has been developed, and this was shown to inhibit cancer cell growth, induce apoptosis in vitro, and also overcome resistance in an imatinib-resistant chronic myeloid leukaemia cell line [8]. POLQ expression is now known to be increased in many cancers but is mostly absent in normal cells, making it a good target for anticancer therapy [9, 10].

References

1. Daud AI, Ashworth MT, Strosberg J et al. Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J Clin Oncol 2015; 33: 1060-1066.
2. Do K, Doroshow JH, Kummar S. Wee1 kinase as a target for cancer therapy. Cell Cycle 2013; 12: 3159-3164.
3. Leijen S, van Geel RM, Pavlick AC et al. Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors. J Clin Oncol 2016; 34: 4371-4380.
4. Tsuji T, Sapinoso LM, Tran T et al. CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitro. Oncotarget 2017; 8: 74688-74702.
5. Gourley C, Balmana J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019; doi: 10.1200/JCO.1218.02050. [Epub ahead of print].
6. Fathers C, Drayton RM, Solovieva S, Bryant HE. Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells. Cell Cycle 2012; 11: 990-997.
7. James D, Jordan A, Hamilton N et al. Pharmacological characterisation of cell active inhibitors of Poly(ADP-ribose) glycohydrolase (PARG). Cancer Res 2014; 74(19 Suppl): Abstract 2745.
8. Zhu J, Zhou L, Wu G et al. A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia. EMBO Mol Med 2013; 5: 353-365.
9. Higgins GS, Prevo R, Lee YF et al. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Cancer Res 2010; 70: 2984-2993.
10. Higgins GS, Boulton SJ. Beyond PARP-POLtheta as an anticancer target. Science 2018; 359: 1217-1218.