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Tubulysins

Written by Susanne Bach. Posted in products

Natural tubulysins and analogues

Our Partner Tube Pharmaceuticals has developed several tubulysins for use in conjugate therapeutics which are produced by fermentation at EUCODIS Bioscience. The potency of Tube’s tubulysin toxins as a conjugate payload allows to target resistant cancers.

The toxins are available in milligram to  gram quantities. Please contact the EUCODIS Bioscience product support for a price offer, additional information on tubulysins and for support on your specific application using our new compounds.

Available toxins are:

  • Tubulysin A
  • Tubulysin B
  • Other natural or synthetic analogues on request

 

Tubulysin A: R1 = CH2CH(CH3)2
Tubulysin B: R1 = CH2CH2CH3

>> Download datasheet

Like auristatins and maytansine, which are used as payloads in antibody-drug conjugates (ADCs), tubulysins are  microtubule-disrupting agents. The recently discovered natural product class of the tubulysins shows a very high cytotoxic activity in in-vitro and in-vivo tumor models, especially in tumor cells resistant against other microtubule destabilizing drugs.

Many representatives of these natural products are several orders of magnitude more potent than other marketed chemotherapeutics such as vincristine, taxanes and others. Based on the structure-activity relationship  of the tubulysins, this class allows many conjugation and targeting strategies: They are well suited for any kind of conjugation to polymers or biomolecules such as e.g. antibodies or proteins.

Tubulysins are a naturally occurring cytotoxic class of peptide compounds which destabilize microtubules and prevent cell growth and division1. Their known biologic activities can be summarized as follows:

  • Tubulysins bind to the vinca domain of tubulin with higher affinity than vinblastine, leading to tubulin depolymerisation, G2/M accumulation and apoptosis2.
  • Tubulysins are approximately 100- to 1000-fold more cytotoxic than traditional chemotherapeutics (e.g. taxol, vinblastine) with EC50 in the nanomolar to sub-nanomolar range.
  • Studies indicate that tubulysins are highly active in multidrug resistant cell lines that either overexpress P-glycoprotein pumps or have tubulin mutations3.
  • Tubulysin A is not a substrate for cytochrome P450 enzymes, making unfavourable drug-drug interactions less likely3.


Crystals of tubulysin A

Picture kindly provided by Prof. G. Hoefle, GBF Braunschweig, Germany

References:
1. J. Antibiotics, 53: 879 (2000); G. Höfle et al.
2. Chembiochem 7:678 (2006); Khalil et al.
3. Biochem. J. 396: 235-242 (2006); A. Dömling et al.

Further reading:
1. Mol. Cancer Ther., 15(5) (2016); P.J. Burke et al.
2. Molec. Div. 141 (2005); A. Dömling, W.Richter
3. Ang. Chem. Intl. Ed. Engl. 4888 (2004); G. Höfle et al.