TDI-011536
目录号 : GC65889TDI-011536 is a potent Lats kinase inhibitor that interrupts Hippo-Yap signaling and promotes proliferation of lesioned cardiac muscle cells.
Cas No.:2687970-96-1
Sample solution is provided at 25 µL, 10mM.
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TDI-011536 is a potent Lats kinase inhibitor that interrupts Hippo-Yap signaling and promotes proliferation of lesioned cardiac muscle cells.
[1] Kastan NR, et al. Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2206113119.
Cas No. | 2687970-96-1 | SDF | Download SDF |
分子式 | C19H16N4O2S | 分子量 | 364.42 |
溶解度 | DMSO : 125 mg/mL (343.01 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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1 mM | 2.7441 mL | 13.7204 mL | 27.4409 mL |
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10 mM | 0.2744 mL | 1.372 mL | 2.7441 mL |
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Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs
Proc Natl Acad Sci U S A 2022 Jul 12;119(28):e2206113119.PMID:35867764DOI:PMC9282237
The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular signals can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily postmitotic and aids regeneration in mammals. In the present study, we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of Yap target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies.