Epothilones

Using our advanced full synthesis “DrugLnk” platform for antibody-drug conjugate (ADC) development, Creative Biolabs offers epothilones conjugated ADCs with the most suitable linkers and optimized conjugation strategies to serve clients’ specific requirements.

Epothilones, commonly referred to as macrolide compounds, were initially discovered in 1987 from the fermentation products of soil bacteria. They are a group of anti-cancer drugs with high potency. Judging from the characteristics of their chemical structures, epothilones can be divided into two classes based on the functional groups on their C12 to C13 positions: epoxide epothilones (epoxides), including epothilones A, B, E and F, have an epoxide structure at the C12-C13 position while olefin epothilones (olefins, including epothilone C and D) have an alkene-cored structure. Structurally, epothilones are less sophisticated than taxanes, another family of chemical payloads often used in ADC development. However, the critical functional groups on epothilones still empower them as good anti-cancer agents. The core structure of an epothilone is a macrolide ring that contains a ketone and a thiazole-containing side chain. Mechanism wise similar to taxanes, epothilones fight cancer cells by interfering with tubulin. However, even with simpler chemical structures, they were reported to have better efficacy yet much moderate adverse effects comparing to taxanes. Another advantage of epothilones over taxanes is their good water solubility. Dissolving and delivering taxanes often require solvents such as cremophors due to their poor solubility. These organic solvents are notorious for their effects on disrupting cardiac function and causing severe hypersensitivity. Thus, high water solubility of epothilones enables their easy delivery and in the meantime, facilitates conjugation, which occurs mainly in aqueous solutions under physiological pH.

Chemical structures of the epothilones under clinical development, including four epoxides (top four) and two olefins (bottom two) (Biologics, 2008).

Epothilones Mode of Action (MOA)

Similar to taxanes, suppression of microtubule function is the main mechanism of action by epothilones. By doing so, epothilones prevent cells from dividing since microtubules are crucial in the process of mitosis. Experimentally, epothilone B exhibits resembling effects on in vitro cultured cells as taxanes, partially due to their common interacting targets. Other studies have shown that epothilone B and taxanes exert similar binding affinity towards microtubule, another piece of evidence contributing to the similarities in cytotoxic effects between epothilone B and taxanes. In terms of microtubule interactions, epothilone B binds to the αβ-tubulin heterodimer subunit, thus stabilizing the microtubules by reducing the dissociation rate of αβ-tubulin. In addition, epothilone B enables tubulin polymerization into microtubules without the presence of GTP. Both mechanisms contribute to the overall effect of epothilone B to restrain spindle function by inhibition of microtubule dynamics.

Taxol (left) and epothilone A (right) binging to β-tubulin. Both toxins reside in a common binding pocket in the intermediate domain of β-tubulin and form H-bonding with several polar amino acids including T274, S275, H227… (PLOS one, 2012).

Epothilones-based ADCs

Epothilones show powerful preclinical and clinical activities in human malignancies and they serve essentially as lead structures in the search for improved anti-cancer drugs. Recently, newly functionalized epothilone analogs for the construction of epothilone-based ADC have been developed with enhanced tumor selectivity. In addition, a therapeutic nanoparticle composed of epothilone B and a biocompatible polymer had been disclosed to serve as an innovative drug delivery system for epothilone B.

Chemical modifications of epothilone B that yield various potent epothilone B derivatives for ADC development (Schiess, 2013)

Creative Biolabs has extensive expertise in ADCs studies with years of experience in customized chemical synthesis and bio-conjugation. With our advanced “DrugLnk” synthesis platform, Creative Biolabs is confident in providing services for the development of highly customized ADCs using epothilones as payloads. In the meantime, Creative Biolabs also provides other various ADC-related services. Please contact us for more information and a detailed quote regarding your ADC design and production.

References:

1. Schiess, R. Total synthesis of cyclopropyl-epothilone B analogs and studies towards the total synthesis of michaolide E. Doctoral dissertation, Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. 21597, 2013.
2. Cheng, K.L.; et al. Novel microtubule-targeting agents-the epothilones. Biologics. 2008, 2(4): 789-811.
3. Bollag, D.M.; et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 1995, 55(11): 2325-2333.
4. Natarajan, K.; et al. Understanding the basis of drug resistance of the mutants of αβ-tubulin dimer via molecular dynamics simulations. PLoS ONE. 2012, 7(8): e42351.