Tubulysins are a class of cytostatic tetrapeptides that were isolated from Myxobacteria (Sasse F et al J. Antibiotics, 2000, 879). The common features of the tubulysins are their tetrapeptidic structure, of which only Ile is naturally occurring amino acid and three others are complex unnatural amino acids: Mep (R—N-Mepipecolic acid), Tuv (tubuvaline) and Tut (tubulyrosine) or Tup (tubuphenylalanine) Later on additional members of the family were described (Steinmettz et al, Angew. Chem. Int. Ed. 2004, 4888). Most naturally occurring tubulysins showed pM cytotoxic activity against cancer cell lines that correlated with tubulin-polymerization inhibition. The mechanism of action of tubulysins was described by Sasse (Khalil M W et al Chem Bio Chem, 2006, 678) which showed that Tubulysin A is more efficacious in inhibiting tubulin polymerization than other vinca domain of beta-tubulin binders (phomopsin, dolastatin and hemiasterlin). Naturally occurring tubulysins showed consistent higher toxicity than dolastatin. Furthermore Tubulysin A was reported (Kaur G et al, Biochem. J, 2006, 235) to induce apoptosis in cancer cell lines and showed antiangiogenic activity in addition to potent antitumor activity in animal models. Following these findings considerable effort was invested into finding synthetic analogs with comparable potency to naturally occurring tubulysins. The presence of N,O-acetal-containing-Tuv has posed a challenge to synthesizing tubulysins and led to concerns regarding their stability. Several groups identified synthetic analogs that replaced the N,O-acetal with a plain methyl group without significant loss of cytotoxic activity (Patterson, A et al, Chem. Eur. J. 2007, 9534; Wipf P et al Org. Lett. 2007, 1605).
Several reports disclose conjugates of tubulysins with folate (Leamon C P et al, Cancer Res. 2008, 9839), cyclodextrin nano-conjugates (Schluep T S et al Clin. Cancer Res. 2009, 15:181) as well as dendrimer conjugates (Floyd W C, Chem Med Chem 2011, 49). One report discloses conjugation of tubulysins to monoclonal antibodies (US2011/0027274).
Novel tubulysin derivatives may be useful as cytotoxic agents to provide therapeutic benefits in the treatment of various types of cancers, alone, as drug conjugates or in combination with other chemotherapies.
USPTO Backgrounds
USPTO Backgrounds