The recent developments of ADCs with the tubulysins as the payloads.

As a novel bio-targeting antitumor agent, an antibody-drug conjugate (ADC) combines the high selectivity of monoclonal antibody and potent cytotoxicity of drug or payload. It can expand the scope of clinical application of small molecule drugs. Tubulysin and its bio-precursor pretubulysin (PT) are potent tubulin-binding antitumor drugs. Due to the excellent antitumoral, antimetastatic, antiangiogenic, and anti-multidrug resistance properties, Tubulysins or PT is believed to be a promising cancer therapeutic approach. Currently, the modifications of tubulysin are centering on the C-11 acetoxyl and N,O-acetal groups, and numerous promising payloads are identified. There are at least 5 sites to introduce appropriate drug linkers in tubulysin and PT for connecting the antibodies. The possible sites of attachment are located in Mep, Tuv, or Tup parts. Cleavage and non-cleavage linkers are used in these ADCs. The chemical reactions involved in the final conjugation of antibody and linker-payload (LP) are cysteine, lysine, site-specific, and click chemistry reactions. In this article, the recent development of ADCs with tubulysins as the payloads is reviewed, with the hope of providing a reference and future strategies for developing new ADSs.