Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores – A cautionary disclosure

Acton, Ben; Small, Helen; Smith, Kate; McGonagle, Alison E.; Stowell, Alexandra; James, Dominic I.; Hamilton, Nial M; Hamilton, Nicola; Hitchin, James R.; Hutton, Colin; Waddell, Ian D.; Ogilvie, Donald; Jordan, Allan M.

doi:10.1016/j.bmcl.2018.12.066

Cited by 3 publications

(4 citation statements)

References 7 publications

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“…In contrast, a total of 24 non-fluorinated compounds were well-tolerated across doses ranging from 5 to 160 mg/kg. Collectively, these results implicated a common metabolite of the fluorinated derivatives as the ultimate toxicant, although the metabolic pathway was not elucidated …”

Section: Fluorinated Aminesmentioning

confidence: 98%

“…Unexpected but strongly adverse effects were associated with oral administration of poly-ADP ribose glycohydrolase (PARG) inhibitors incorporating an N-(1-(fluoromethyl)cyclopropyl)sulfonamide substructure, with observations suggesting a role for gut metabolism on the basis of the absence of toxicity following iv dosing. 274 As background, 335 and 336 exhibited short half-lives in vivo that precluded evaluation in animal efficacy models. Subsequent in vitro studies identified the sulfonamide substituent as the major site of metabolism, giving rise to the primary sulfonamide (RSO 2 NH 2 ).…”

Section: T H Imentioning

confidence: 99%

“…Collectively, these results implicated a common metabolite of the fluorinated derivatives as the ultimate toxicant, although the metabolic pathway was not elucidated. 274 5.5. PLP-Dependent Metabolism of β-Fluorinated Amines.…”

Section: T H Imentioning

confidence: 99%

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Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

et al. 2020

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The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C–F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compounds. In this Perspective, we summarize the literature associated with the metabolism of fluorinated molecules, focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.

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Section: Fluorinated Aminesmentioning

confidence: 98%

Section: T H Imentioning

confidence: 99%

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Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

et al. 2020

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“…In this study, we have provided preclinical evidence that CCNE1 could be a predictive biomarker for a response to PARGi in breast cancer. To date, no PARGi has entered the clinic and no in vivo inhibitors has been identi ed yet, potentially owing to poor pharamacokinetic and phamracodynamic properties in vivo including a short half-life and lack of sustained target coverage 37 . Further work will be required to optimize this class of compounds for use in vivo and ultimately for use in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Synthetic lethality between CCNE1 hyperactivity and PARG inhibition in breast cancer

Bandyopadhyay

Jacobo

2022

Preprint

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Poly(ADP-Ribose) polymerase (PARP) inhibitors have shown wide utility in targeting cancers with defects in homologous recombination. Poly(ADP-ribose) glycohydrolase (PARG), reverses the action of PARP enzymes and may also be an anti-cancer target. Genetic mapping of cellular factors dictating response to a PARG inhibitor by siRNA and CRISPR screens revealed chemical synthetic lethality with loss of base excision repair (BER) machinery also reflected in synergies with therapeutics that induce BER-dependent DNA damage. In a pharmacogenomic screen, Cyclin E1 (CCNE1) expression predicted PARG inhibitor efficacy across a panel of breast cancer cell lines and genetic induction of CCNE1 leads to drug sensitivity. PARG inhibitors cause excessive PAR formation, resulting in loss of cellular NAD + leading to necrosis. Hence, PARG inhibitors selectively kill cells with elevated PAR turnover, by impinging on the BER pathway or CCNE1-induced replication stress, and stalling PAR recycling may lead to runaway PAR accumulation and energy dependent cell death.

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