Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction

Jong Hyun Kim, Chulho Lee, Minji Lee, Haipeng Wang, Kibum Kim, Seung Joon Park, Ina Yoon, Jayun Jang, Hanchao Zhao, Hoi Kyoung Kim, Nam Hoon Kwon, Seung Jae Jeong, Hee Chan Yoo, Jae Hyun Kim, Jee Sun Yang, Myeong Youl Lee, Chang Woo Lee, Jieun Yun, Soo Jin Oh, Jong Soon Kang, Susan A. Martinis, Kwang Yeon Hwang, Min Guo, Gyoonhee Han, Jung Min Han & Sunghoon Kim


Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiological significance of its activity is not well understood. Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. We identified compounds that inhibit the leucine-dependent mTORC1 pathway by specifically inhibiting the GTPase activating function of LRS, while not affecting the catalytic activity. For further analysis, we selected one compound, BC-LI-0186, which binds to the RagD interacting site of LRS, thereby inhibiting lysosomal localization of LRS and mTORC1 activity. It also effectively suppressed the activity of cancer-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. These findings suggest new strategies for controlling tumor growth that avoid the resistance to existing mTOR inhibitors resulting from cancer-associated MTOR mutations.

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