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Review, Journal: Insulin sensitizers in 2023: lessons learned and new avenues for investigation. (Pubmed Central) - Sep 27, 2023 Pioglitazone remains the best in class with beneficial pleiotropic pharmacology, although use is limited by tolerability issues...Greater understanding of the mechanism of action of insulin sensitizing drugs can expand the rationale for the fields of treatment and potential for treatment combinations. This understanding can facilitate the registration and broader use of agents with that impact the pathophysiology that underlies chronic metabolic diseases as well as host responses to environmental insults including pathogens, insulin sensitizer, MPC, mitochondrial target, metabolic reprogramming, chronic and infectious disease.
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Journal: Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells. (Pubmed Central) - Aug 21, 2023 Finally, we demonstrate that MSDC-0160, a clinical orally-available MPC1/2 inhibitor, inhibits pyruvate anaplerosis and targets imatinib-resistant CML LSCs in robust pre-clinical CML models. Collectively these results highlight pyruvate anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient-derived samples.
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Journal: Mitoglitazone ameliorates renal ischemia/reperfusion injury by inhibiting ferroptosis via targeting mitoNEET. (Pubmed Central) - Mar 28, 2023 Mechanistically, molecular docking and surface plasmon resonance experiments demonstrated that MGZ exhibited a high binding affinity with the mitochondrial outer membrane protein mitoNEET. Collectively, our findings indicated the renal protective effect of MGZ was closely linked to regulating the mitoNEET-mediated ferroptosis pathway, thus offering potential therapeutic strategies for ameliorating I/R injuries.
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Surprising discoveries while using deuterium to stabilize enantiomers for chiral switching (Room 6D (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_7324; Below are highlights of the effects observed with several racemic compounds including pioglitazone, mitoglitazone, inolitazone, prasugrel, donepezil, lenalidomide, avadomide, iberdomide, and bupropion.Stabilization with deuterium may vary:- by compound even within the same compound class (e.g., thiazolidinediones); and- as a function of stereochemistry (sometimes there is no stabilization for one of the enantiomers).To date, the effects observed when deuterium is used to stabilize enantiomers include:1...Reduced rates of degradation – in addition to reduced enantiomerization (e.g., degradation of thalidomide analogs varies from none to 4x).3...Stereoselective formation of one protonated enantiomer versus the other due to different reaction kinetics (e.g. d-R forms predominately h-R vs h-S).5. Sometimes limited predictive value for in vivo effects of in vitro D/H exchange and enantiomerization studies.
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Journal: Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. (Pubmed Central) - Jun 16, 2019 In turn, we apply a clinically viable small molecule targeting the MPC, MSDC0160, to pre-clinical PCa models and find that MPC inhibition suppresses tumor growth in hormone-responsive and castrate-resistant conditions. Collectively, our findings characterize the MPC as a tractable therapeutic target in AR-driven prostate tumors.
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