In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 4050-4050
Abstract:
Duocarmycins are natural DNA alkylators which have potent toxicity with no established mechanism of resistance. Prodrug versions need to be developed to ensure a sufficient therapeutic window for cancer treatment (1). A series of duocarmycin bioprecursors have been developed in-house which lack a key hydroxyl trigger group, required for spirocyclisation and subsequent activation. This hydroxyl group can be regioselectivity restored by specific Cytochrome P450 enzymes (CYPs), with a primary focus on cancer associated isoforms CYP1A1 and CYP2W1 (2). An exploratory library of analogues of our lead compound, ICT2700 (CYP1A1 and CYP2W1 activated), has been synthesized and elucidated aspects of the structure-activity relationship (SAR) between the compound and subsequent toxicity in CYP transfected and mock cell lines, using MTT assays. The data shows the importance of having an indole in the DNA recognition subunit (the non-alkylating subunit) for CYP1A1 and CYP2W1 activation. Further, a compound with thus far unexplained activity was identified. ICT11038 has a benzofuran instead of an indole in the recognition subunit and subsequently demonstrates inherent nanomolar toxicity consistently in all cell lines tested, including a range of cancerous and non-cancerous cells, which is not dependent on cytochrome expression. CYP1A1 has been shown to enhance the toxicity of ICT11038 further but is not required for nanomolar toxicity. Further SAR exploration and western blots confirm that the inherent toxicity is achieved through DNA damage despite lacking the key trigger group, suggesting a novel activation pathway. Additionally, our SAR studies show that replacing the indole of the DNA alkylation subunit with a benzofuran ablates CYP dependent activity, with one exception, ICT2724. ICT2724 is non-toxic in mock transfected cells but is toxic in CYP1A1 transfected cells, albeit it at higher concentration than ICT2700. ICT2724 is analogous to ICT2700, except for the direct indole to benzofuran substitution. Other compounds with benzofurans in the alkylating subunit compounds are not metabolized to a toxic compound by CYP1A1 or CYP2W1 despite their indole equivalents being good prodrug candidates. To conclude, the introduction of the benzofuran functional group into the CYP-activated duocarmycin bioprecursor pharmacophores produces an unexplained pattern of CYP activation and, in one example, an intrinsically toxic DNA damaging agent (ZYP-11038). References (1) Z. Jukes et al, Drug Discov Today, 2020, 26(2), 577-584, https://doi.org/10.1016/j.drudis.2020.11.020 (2) H. Sheldrake et al, J. Med. Chem, 2013, 56(16); 6273-6277, dx.doi.org/10.1021/jm4000209 Citation Format: Zoe H. Jukes. Effect of benzofuran pharmacophores on CYP-activated duocarmycin bioprecursors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4050.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-4050
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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