Recent advances of the mechanistic target of rapamycin (mTOR) inhibitors for drug discovery.

The mechanistic target of rapamycin (mTOR), a serine/threonine kinase, serves as a central regulator of cellular growth, proliferation, metabolism, and survival through its two distinct multiprotein complexes, mTORC1 and mTORC2. Aberrant activation of the mTOR signaling pathway is frequently implicated in a wide range of human cancers and is closely associated with tumor progression, therapeutic resistance, and poor clinical outcomes. Accordingly, pharmacological inhibition of mTOR has emerged as a compelling strategy in the development of anticancer therapeutics. To date, several mTOR inhibitors have received regulatory approval or are currently undergoing clinical evaluation. This review provides an up-to-date development of small-molecule mTOR inhibitors from 2019 to the present. Emphasis is placed on their structural classification, mechanisms of action, and medicinal chemistry optimization strategies. We believe that this review, together with previous summaries from other research groups, will offer valuable insights to support the rational design and development of next-generation mTOR inhibitors with improved pharmacokinetic properties and enhanced target selectivity.