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Publication Abstract from PubMed

Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling.

Phenotypic screen identifies calcineurin-sparing FK506 analogs as BMP potentiators for treatment of acute kidney injury.,Larraufie MH, Gao X, Xia X, Devine PJ, Kallen J, Liu D, Michaud G, Harsch A, Savage N, Ding J, Tan K, Mihalic M, Roggo S, Canham SM, Bushell SM, Krastel P, Gao J, Izaac A, Altinoglu E, Lustenberger P, Salcius M, Harbinski F, Williams ET, Zeng L, Loureiro J, Cong F, Fryer CJ, Klickstein L, Tallarico JA, Jain RK, Rothman DM, Wang S Cell Chem Biol. 2021 Apr 17. pii: S2451-9456(21)00156-2. doi:, 10.1016/j.chembiol.2021.04.001. PMID:33894161^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.