&lt;p&gt;Metabolic Stability Assessment of New PARP Inhibitor Talazoparib Using Validated LC–MS/MS Methodology: In silico Metabolic Vulnerability and Toxicity Studies&lt;/p&gt;

Attwa, Mohamed W.; Kadi, Adnan A.; Alhazmi, Hassan A.

doi:10.2147/dddt.s239458

Cited by 41 publications

(25 citation statements)

References 24 publications

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“…The CSL was 0.9983, which is considered high compared to other previously studied anti-cancer drugs (ex. Talazoparib) [30]. The outcomes from the WhichP450™ module of StarDrop software revealed that CYP3A4 was found to have a basic role in TEP metabolism, which proposed the high possibility of drug-drug interaction with other drugs that induce or inhibit CYP3A4 enzyme.…”

Section: Results Of In Silico Tep Metabolites Predictionmentioning

confidence: 99%

Identification of Iminium Intermediates Generation in the Metabolism of Tepotinib Using LC-MS/MS: In Silico and Practical Approaches to Bioactivation Pathway Elucidation

Attwa

Kadi

2020

Molecules

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Tepotinib (Tepmetko™, Merck) is a potent inhibitor of c-Met (mesenchymal−epithelial transition factor). In March 2020, tepotinib (TEP) was approved for use in Japan for the treatment of patients who suffered from non-small cell lung cancers (NSCLC) harboring an MET exon 14 skipping alteration and have progressed after platinum-based therapy. Practical and in silico experiments were used to screen for the metabolic profile and reactive intermediates of TEP. Knowing the bioactive center and structural alerts in the TEP structure helped in making targeted modifications to improve its safety. First, the prediction of metabolism vulnerable sites and reactivity metabolic pathways was performed using the StarDrop WhichP450™ module and the online Xenosite reactivity predictor tool, respectively. Subsequently, in silico data were used as a guide for the in vitro practical work. Second, in vitro phase I metabolites of TEP were generated from human liver microsome (HLM) incubations. Testing for the generation of unstable reactive intermediates was performed using potassium cyanide as a capturing agent forming stable cyano adduct that can be characterized and identified using liquid chromatography tandem mass spectrometry (LC-MS/MS). Third, in silico toxicity assessment of TEP metabolites was performed, and structural modification was proposed to decrease their side effects and to validate the proposed bioactivation pathway using the DEREK software. Four TEP phase I metabolites and four cyano adducts were characterized. The reactive intermediate generation mechanism of TEP may provide an explanation of its adverse reactions. The piperidine ring is considered a structural alert for toxicity as proposed by the DEREK software and a Xenosite reactivity model, which was confirmed by practical experiments. Steric hindrance or isosteric replacement at α-carbon of the piperidine ring stop the bioactivation sequence that was confirmed using the DEREK software. More drug discovery studies can be performed using this perception permitting the design of new drugs with an increased safety profile. To our knowledge, this is the first study for the identification of in vitro phase I metabolites and reactive intermediates in addition to toxicological properties of the metabolites for TEP that will be helpful for the evaluation of TEP side effects and drug–drug interactions in TEP-treated patients.

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Section: Results Of In Silico Tep Metabolites Predictionmentioning

confidence: 99%

Identification of Iminium Intermediates Generation in the Metabolism of Tepotinib Using LC-MS/MS: In Silico and Practical Approaches to Bioactivation Pathway Elucidation

Attwa

Kadi

2020

Molecules

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“…Hence, the detection sensitivity decreases when using MS/MS for scanning of unknown metabolites, limiting its usage. However, in case of metabolic stability studies, triple quadrupole instruments provide an excellent alternative to more expensive TOF/Q‐TOF analyzers, enabling both a reliable quantitative analysis (for metabolic stability estimation) and metabolite structure identification [11–19,23,52–60].…”

Section: Separation Techniques Used In Metabolic Stability Estimationmentioning

confidence: 99%

“…In paid options, Stardrop software seems to be one of the most valuable options. Apart from predicting sites of metabolism, Stardrop can also predict P450 metabolism, and is a valuable in silico tool to develop ADME QSAR models and explore metabolism in many creative pathways, depending on the chosen package [54,58,64,93–96].…”

Section: Chemometric Techniques Used In Metabolic Stability Model Devmentioning

confidence: 99%

Metabolic stability studies of lead compounds supported by separation techniques and chemometrics analysis

Ulenberg

Bączek

2020

J of Separation Science

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With metabolism being one of the main routes of drug elimination from the body (accounting for removal of around 75% of known drugs), it is crucial to understand and study metabolic stability of drug candidates. Metabolically unstable compounds are uncomfortable to administer (requiring repetitive dosage during therapy), while overly stable drugs increase risk of adverse drug reactions. Additionally, biotransformation reactions can lead to formation of toxic or pharmacologically active metabolites (either less‐active than parent drug, or even with different action). There were numerous approaches in estimating metabolic stability, including in vitro, in vivo, in silico, and high‐throughput screening to name a few. This review aims at describing separation techniques used in in vitro metabolic stability estimation, as well as chemometric techniques allowing for creation of predictive models which enable high‐throughput screening approach for estimation of metabolic stability. With a very low rate of drug approval, it is important to understand in silico methods that aim at supporting classical in vitro approach. Predictive models that allow assessment of certain biological properties of drug candidates allow for cutting not only cost, but also time required to synthesize compounds predicted to be unstable or inactive by in silico models.

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“…Thus, nucleophile trapping can be utilized to seize the generated reactive species forming stable adducts that could be characterized using liquid chromatography-tandem mass spectrometry (LC-MS/MS). [23][24][25][26] The IUPAC designation of ESB is 6-amino-5- Figure 1). ESB chemical structure contains a dichloro-fluorophenyl ring and cyclic tertiary amine rings (piperazine).…”

Section: Introductionmentioning

confidence: 99%

<p>Characterization of Stable and Reactive Metabolites of the Anticancer Drug, Ensartinib, in Human Liver Microsomes Using LC-MS/MS: An in silico and Practical Bioactivation Approach</p>

Attwa

Kadi

2020

DDDT

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Background: Ensartinib (ESB) is a novel anaplastic lymphoma kinase inhibitor (ALK) with additional activity against Abelson murine leukemia (ABL), met proto-oncogene (MET), receptor tyrosine kinase (AXL), and v-ros UR2 sarcoma virus oncogene homolog 1 (ROS1) and is considered a safer alternative for other ALK inhibitors. ESB chemical structure contains a dichloro-fluorophenyl ring and cyclic tertiary amine rings (piperazine) that can be bioactivated generating reactive intermediates. Methods: In vitro metabolic study of ESB with human liver microsomes (HLMs) was performed and the hypothesis of generating reactive intermediates during metabolism was tested utilizing trapping agents to capture and stabilize reactive intermediates to facilitate their LC-MS/MS detection. Reduced glutathione (GSH) and potassium cyanide (KCN) were utilized as trapping agents for quinone methide and iminium intermediates, respectively. Results: Four in vitro ESB phase I metabolites were characterized. Three reactive intermediates including one epoxide and one iminium intermediates were characterized. ESB bioactivation is proposed to occur through unexpected metabolic pathways. The piperazine ring was bioactivated through iminium ions intermediates generation, while the dichlorophenyl group was bioactivated through a special mechanism that was revealed by LC-MS /MS. Conclusion: These findings lay the foundations for additional work on ESB toxicity. Substituents to the bioactive centers (piperazine ring), either for blocking or isosteric replacement, would likely block or interrupt hydroxylation reaction that will end the bioactivation sequence.

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<p>Metabolic Stability Assessment of New PARP Inhibitor Talazoparib Using Validated LC–MS/MS Methodology: In silico Metabolic Vulnerability and Toxicity Studies</p>

Cited by 41 publications

References 24 publications

Identification of Iminium Intermediates Generation in the Metabolism of Tepotinib Using LC-MS/MS: In Silico and Practical Approaches to Bioactivation Pathway Elucidation

Identification of Iminium Intermediates Generation in the Metabolism of Tepotinib Using LC-MS/MS: In Silico and Practical Approaches to Bioactivation Pathway Elucidation

Metabolic stability studies of lead compounds supported by separation techniques and chemometrics analysis

<p>Characterization of Stable and Reactive Metabolites of the Anticancer Drug, Ensartinib, in Human Liver Microsomes Using LC-MS/MS: An in silico and Practical Bioactivation Approach</p>

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