Tubulysin analogs and methods for their preparation
The present invention is directed to novel cytotoxic tubulysin analogs and derivatives, to antibody drug conjugates thereof, and to methods for using the same to treat medical conditions including cancer.
1. A compound presented below:
or a pharmaceutically acceptable salt thereof.
2. A compound selected from:
or a pharmaceutically acceptable salt thereof.
3. A compound selected from:
where X is an antibody, or a pharmaceutically acceptable salt thereof.
4. The compound or salt of claim 3 , wherein said antibody is selected from: trastuzumab, trastuzumab mutants, oregovomab, edrecolomab, cetuximab, a humanized monoclonal antibody to the vitronectin receptor (α v β 3 ), alemtuzumab, a humanized anti-HLA-DR antibody for the treatment of non-Hodgkin's lymphoma, 131I Lym-1, a murine anti-HLA-Dr10 antibody for the treatment of non-Hodgkin's lymphoma, a humanized anti-CD2 mAb for the treatment of Hodgkin's Disease or non-Hodgkin's lymphoma, labetuzumab, bevacizumab, ibritumomab tiuxetan, ofatumumab, panitumumab, rituximab, tositumomab, ipilimumab, gemtuzumab, humanized monoclonal antibody to the oncofecal protein receptor 5T4, M1/70 (antibody to CD11b receptor), and other antibodies.
5. The compound of claim 3 , wherein the antibody is bound via a Fc-containing or Fab-containing polypeptide engineered with an acyl donor glutamine-containing tag or an endogenous glutamine made reactive by polypeptide engineering in the presence of transglutaminase.
6. A pharmaceutical composition comprising an effective amount of the compound or salt of claim 3 , or a pharmaceutically acceptable diluent, carrier or excipient.
7. The pharmaceutical composition of claim 6 , further comprising a therapeutically effective amount of a chemotherapeutic agent selected from the group consisting of a tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA binder.