Description:
METHOD TO INHIBIT MUSCLE WASTING
Nilotinib (TasignaTM) an off patent, FDA-approved kinase inhibitor has been used by UTHealth investigators at a significantly lower than approved dose as a treatment for muscle wasting. This suggests great potential as a therapeutic for syndromes such as cancer-associated cachexia and sarcopenia.
At 500 nM in vitro, it abrogates muscle catabolism without suppressing myogenesis mediated by p38β MAPK, and systemic administration of nilotinib at a low dose of 0.5 mg/kg/day alleviates muscle wasting and prolongs lifespan in tumor-bearing mice.
Background
Cachexia, characterized by muscle wasting, is a lethal metabolic syndrome without defined etiology and established treatment. Researchers at UTHealth previously found that p38β MAPK is essential for muscle wasting induced by circulating Hsp70/90 and inflammatory cytokines elevated in cancer, other inflammatory diseases and sarcopenia. As an effector of TLR4 and many cytokine receptors, p38β MAPK activates p300, C/EBPβ and ULK1 to stimulate muscle protein loss mediated by the ubiquitin-proteasome and autophagy-lysosome pathways. Thus, p38β MAPK is a central mediator and therapeutic target of cancer and other inflammatory condition-induced muscle wasting.
Technology Highlights
• Nilotinib, an FDA-approved kinase inhibitor that preferentially binds p38β MAPK (Kd 32 nM) abrogates cancer-induced muscle catabolism at 500 nM in vitro:
• ~20-fold more potent than the p38α/β MAPK inhibitor SB202190
• without suppressing myogenesis mediated by p38a MAPK
• Systemic administration of nilotinib in vivo at a low dose of 0.5 mg/kg/day
alleviates muscle wasting and prolongs lifespan in tumor-bearing mice.
Intellectual Property Status
• Patent pending
• Available for licensing
Stage of Development
Preclinical
About the Investigator
Yi-Ping Li, Ph.D., is a Professor in the Department of Integrative Biology and Pharmacology at McGovern Medical School at UTHealth, Houston Texas. His research interests focus on signaling mechanisms of striated muscle remodeling.