ArticleBirth defects research2022
Malarial PI4K inhibitor induced diaphragmatic hernias in rat: Potential link with mammalian kinase inhibition.
Article in Birth defects research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
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- Clinical Potential of Misshapen/NIKs-Related Kinase (MINK) 1-A Many-Sided Element of Cell Physiology and Pathology.Current issues in molecular biology · 2024Review
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- 2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors ofJournal of medicinal chemistry · 2024Article
- Recent advances, challenges and updates on the development of therapeutics for malaria.EXCLI journal · 2024Review
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
- Modelling PIP4K2A inhibitory activity of 1,7-naphthyridine analogues using machine learning and molecular docking studies.RSC advances · 2023Article
- Malarial PI4K inhibitor induced diaphragmatic hernias in rat: Potential link with mammalian kinase inhibition.Birth defects research · 2022Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMMV390048 is an aminopyridine plasmodial PI4K inhibitor, selected as a Plasmodium blood-stage schizonticide for a next generation of malaria treatments to overcome resistance to current therapies. MMV390048 showed an acceptable preclinical safety profile and progressed up to Phase 2a clinical trials. However, embryofetal studies revealed adverse developmental toxicity signals, including diaphragmatic hernias and cardiovascular malformations in rats but not rabbits.
methodsIn vivo exposures of free plasma concentrations of compound in rats were assessed in relation to in vitro human kinase inhibition by MMV390048, using the ADP-Glo™ Kinase Assay.
resultsWe demonstrate a potential link between the malformations seen in the embryofetal developmental (EFD) studies and inhibition of the mammalian PI4Kβ paralogue, as well as inhibition of the off-target kinases MAP4K4 and MINK1. PI3Kγ may also play a role in the embryofetal toxicity as its in vitro inhibition is covered by in vivo exposure. The exposures in the rabbit embryofetal development studies did not reach concentrations likely to cause PI4K inhibition. Overall, we hypothesize that the in vivo malformations observed could be due to inhibition of the PI4K target in combination with the off-targets, MAP4K4 and MINK1. However, these relationships are by association and not mechanistically proven.
conclusionsDeciphering if the EFD effects are dependent on PI4K inhibition, and/or via inhibition of other off-target kinases will require the generation of novel, more potent, and more specific PI4K inhibitors.
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