Creative Biolabs is a pioneer in antibody-drug conjugate (ADC) development and our science team provides customized ADCs with tubulysins as payload drugs using suitable linkers and optimized conjugation strategies.

Tubulysins, originally isolated from myxobacteria, are a series of antimitotic tetrapeptides discovered by Hofle and co-workers in 2000. Functionally similar to dolastatins, tubulysins are among the most powerful cell division inhibitors reported until now. Due to their ability to inhibit tubulin polymerization, tubulysins exert a potent anti-proliferative activity against human cancer cells, even the drug-resistant cancer cells. So far, 14 different tubulysin isoforms have been reported and their conserved core structure, containing a secondary alcohol or acetate at C-11, is comprised of a L-isoleucine (Ile), a tubuvaline (Tuv) and a N-methylD-pipecolic acid (Mep) unit. All natural tubulysins have a special N,O-acetal and either a tubutyrosine (Tut) or a tubuphenylalanine (Tup) at the C-termini for their biological function. Meanwhile, it has been demonstrated that the N,O-acetal can be replaced by a plain alkyl group to offer N-14-desacetoxytubulysin H without any loss in potency.

Tubulysins Structures of tubulysin and a variety of tubulysin derivatives (J. Org. Chem, 2016).

Tubulysins Mode of Action (MOA)

Tubulysins inhibit cancer progression by their powerful microtubule inhibition (MTI) capabilities. Upon release, tubulysis rapidly decompose the cytoskeleton and mitotic machinery of dividing cancer cells, resulting in apoptosis. With their remarkable cytotoxic activity, tubulysins have been exploited to target numerous human cancer lines. What’s more, tubulysins have also been demonstrated to be effective on multi-drug-resistant (MDR) carcinoma cell lines. Taken together, with their high cytotoxic potency against a broad spectrum of cancer cells, especially the MDR cells, tubulysins have been a favored choice as payloads for the selective targeting of cancer cells through ADCs and Small Molecule Drug Conjugates (SMDCs).

Tubulysin mode of action—decomposing microtubules and restraining mitosis of treated cells. Left: control sample without tubulysin treatment, right: several hours of tubulysin treatment disrupted the cytoskeleton and inhibited the formation of the mitotic spindle (ChemBioChem, 2006).

Tubulysins-based ADCs

Taking advantage of the high folate receptor expression in a number of cancers, tubulysin B–folic acid conjugate (EC0305, 79) was the first targeted drug involving tubulysin. Since then, multiple ADCs carrying tubulysin analog payloads have been exploited. Tubulysin D, one of the most potent member of the tubulysins family, is able to cause multipolar spindles and it was initially conjugated with polymers to offer proof-of-concept studies in preclinical models. Currently, several ADCs bearing tubulysin D payload are under active development. With high target specificity empowered by monoclonal antibodies, these ADCs deliver tubulysin selectively to cancer cells, therefore averting toxic effects on normal tissues.

Chemical structures of tubulysin analogues TUB-OH and TUB-OMOM and their radioiodination, esterification, and conjugation to a mAb. Two synthetic tubulysin A analogues, TUB-OMOM and the less potent TUB-OH, were modified by 131I-radioiodination and NHS ester activation. They were subsequently conjugated to non-labeled or 89Zr-labeled Trastuzumab via Lys residues (amine reaction) to form single or dual radiolabeled ADCs (Cancer Res., 2014)

With our well-established “DrugLnk” organic synthesis platform, the experienced scientists here at Creative Biolabs is dedicated to help you develop tubulysin-linker complexes using readily available or customized linkers for ADC developments in a timely and cost-effective manner. Our customarily tailored services and high quality products will contribute greatly to the success of your projects.

Creative Biolabs also provides other various services regarding ADC development. Please feel free to contact us for more information and a detailed quote.


  1. Cohen, R.; et al. Development of novel ADCs: Conjugation of tubulysin analogues to trastuzumab monitored by dual radiolabeling. Cancer Res. 2014, 74(20): 5700-5710.
  2. Murray, B.C.; et al. Chemistry and biology of tubulysins: antimitotic tetrapeptides with activity against drug resistant cancers. Nat. Prod. Rep. 2015, 32(5): 654-662.
  3. Colombo, R.; et al. Total synthesis and biological evaluation of tubulysin analogues. J. Org. Chem. 2016, 81: 10302−10320.
  4. Khalil, M.W.; et al. Mechanism of action of tubulysin, an antimitotic peptide from Myxobacteria. ChemBioChem. 2006, 7: 678 – 683.

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