Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth.
Nat Chem Biol, 2021/10;17(10):1065-1074.
Lee BJ[1], Boyer JA[2, 3], Burnett GL[4], Thottumkara AP[4], Tibrewal N[5], Wilson SL[1], Hsieh T[5], Marquez A[5], Lorenzana EG[1], Evans JW[1], Hulea L[6, 7, 8], Kiss G[5], Liu H[9], Lee D[10], Larsson O[9], McLaughlan S[6], Topisirovic I[6], Wang Z[10], Wang Z[10], Zhao Y[10], Wildes D[1], Aggen JB[4], Singh M[1], Gill AL[4], Smith JAM[11], Rosen N[12]
Affiliations
PMID: 34168367DOI: 10.1038/s41589-021-00813-7
Impact factor: 16.174
Abstract
The clinical benefits of pan-mTOR active-site inhibitors are limited by toxicity and relief of feedback inhibition of receptor expression. To address these limitations, we designed a series of compounds that selectively inhibit mTORC1 and not mTORC2. These 'bi-steric inhibitors' comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. Structural modification of these components modulated their affinities for their binding sites on mTOR and the selectivity of the bi-steric compound. mTORC1-selective compounds potently inhibited 4EBP1 phosphorylation and caused regressions of breast cancer xenografts. Inhibition of 4EBP1 phosphorylation was sufficient to block cancer cell growth and was necessary for maximal antitumor activity. At mTORC1-selective doses, these compounds do not alter glucose tolerance, nor do they relieve AKT-dependent feedback inhibition of HER3. Thus, in preclinical models, selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation as compared to pan-mTOR inhibitors.
MeSH terms
Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Drug Design; Female; Gene Expression Regulation; Humans; Mechanistic Target of Rapamycin Complex 1; Structure-Activity Relationship
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