Identification of different side effects between PARP inhibitors and their polypharmacological multi‐target rationale

Sandhu, Daranjit; Antolín, Albert A.; Cox, Anthony R.; Jones, Alan M.

doi:10.1111/bcp.15015

Cited by 46 publications

(42 citation statements)

References 62 publications

(105 reference statements)

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“…The effect of a polypharmacology in this context is still unknown, and selectivity over the other PARPs may not even be in all cases the most beneficial property of a drug candidate in a clinical setting. 169 On the contrary, to be useful as a chemical probe for the analysis of the biological response and in proof-of-concept in vivo studies, high specificity of the inhibitor is important. The lack of access to a complete panel of sensitive, high-throughput PARP assays 117 , 170 − 172 to fully evaluate selectivity is a common weakness that leads to profiling of PARP inhibitors only against a handful of family members, rarely including representative mono-ARTs.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

“…PARP1 is generally considered the major target of the FDA-approved PARPi, but due to the structural similarity of the targeted NAD + -binding domain, they also inhibit the activity of other PARPs, mainly PARP2. The effect of a polypharmacology in this context is still unknown, and selectivity over the other PARPs may not even be in all cases the most beneficial property of a drug candidate in a clinical setting . On the contrary, to be useful as a chemical probe for the analysis of the biological response and in proof-of-concept in vivo studies, high specificity of the inhibitor is important.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

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Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

et al. 2022

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Major advances have recently defined functions for human mono-ADP-ribosylating PARP enzymes (mono-ARTs), also opening up potential applications for targeting them to treat diseases. Structural biology combined with medicinal chemistry has allowed the design of potent small molecule inhibitors which typically bind to the catalytic domain. Most of these inhibitors are at the early stages, but some have already a suitable profile to be used as chemical tools. One compound targeting PARP7 has even progressed to clinical trials. In this review, we collect inhibitors of mono-ARTs with a typical “H–Y−Φ” motif (Φ = hydrophobic residue) and focus on compounds that have been reported as active against one or a restricted number of enzymes. We discuss them from a medicinal chemistry point of view and include an analysis of the available crystal structures, allowing us to craft a pharmacophore model that lays the foundation for obtaining new potent and more specific inhibitors.

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

et al. 2022

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“…Neurological and cardiovascular disorders, including headache, insomnia, hypertension and tachycardia/palpitations, have been reported with all PARP inhibitors and also with ATR, CHK1 and WEE1 targeting agents, with a variable incidence ( Table 2 ). According to pre-clinical evidence, activation of PARP enzymes in the central nervous system seems to have a role in neuronal death and circadian regulation, which could explain the headache and insomnia observed with PARP inhibitors [ 63 , 64 ], while niraparib interaction with dopamine, noradrenaline and serotine transporters as well as with the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) receptor could justify the cardiovascular effects of this drug [ 65 ].…”

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

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“…21 Understanding the pharmacology of a drug may help predict ADR prevalence as unwanted protein-drug interactions can have unintended consequences in certain patient populations. [22][23][24] Studies have assessed ARB ADRs 2 but the relationship between the pharmacology of ARBs and their respective ADRs has yet to be investigated. Furthermore, recent media attention regarding the detection of potential carcinogens in specific ARB products warranted an application of our technique to understand the potential relationship between ARB ADRs and the presence of a mutagenic contaminant in certain batches.…”

Section: Introductionmentioning

confidence: 99%

“…Understanding the pharmacology of a drug may help predict ADR prevalence as unwanted protein–drug interactions can have unintended consequences in certain patient populations 22–24 . Studies have assessed ARB ADRs 2 but the relationship between the pharmacology of ARBs and their respective ADRs has yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II receptor blockers (ARBs) and manufacturing contamination: A retrospective National Register Study into suspected associated adverse drug reactions

Salim

Jones

2022

Brit J Clinical Pharma

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The aim of this study was to determine if any suspected adverse drug reactions (ADRs) observed with the use of angiotensin II receptor blockers (ARBs) could be linked to either (a) their unique respective physicochemical and pharmacological profiles and (b) the recently disclosed suspected carcinogenic manufacturing contaminants found in certain sartan drug class batches. Methods:The pharmacology profiles of ARBs were data-mined from the Chemical Database of bioactive molecules with drug-like properties, European Molecular Biology Laboratory (ChEMBL). Suspected ADR data (from 01/2016-10/2022, inclusive) and prescribing rates of ARBs over a 5-year prescribing window (from 09/2016 to 08/2021, inclusive) were obtained via analysis of the United Kingdom Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profile and Open prescribing databases, respectively. Results:The overall suspected ADRs and fatalities per 100 000 prescriptions identified across the ARBs studied were found to be different between the sartan drug class members (chi-squared test, P < .05). There is a greater relative rate of reports for valsartan across all investigated organ classes of ADRs, than other ARBs, despite valsartan's more limited pharmacological profile and similar physicochemical properties to other sartans. The disparity in ADR reporting rates with valsartan vs other ARBs could be due to the dissimilarity in formulation excipients, patient factors and publicity surrounding batch contaminations, amongst others. Cancer-related ADRs and fatalities per 100 000 prescriptions identified across the ARBs studied are not statistically significant (chi-squared test, P > .05) based on the datasets used over the 5-year period. Conclusion:No connection between ARB pharmacology and their suspected ADRs could be found. No conclusion between sartan batch contaminations and increased suspected cancer-related ADRs was found.

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Identification of different side effects between PARP inhibitors and their polypharmacological multi‐target rationale

Cited by 46 publications

References 62 publications

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Angiotensin II receptor blockers (ARBs) and manufacturing contamination: A retrospective National Register Study into suspected associated adverse drug reactions

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