Thailanstatin A

Creative Biolabs provides spliceosome inhibitors such as thailanstatin A as payloads for antibody-drug conjugates (ADCs) development services. With our well-established “DrugLnk” organic synthesis platform, our scientists offer highly customized ADCs with optimized linkers and the most suitable conjugation strategies.

Splicing is a mRNA processing step during which introns are removed from the pre-mRNAs while exons are ligated to form a mature mRNA molecule. Enhancer and suppressor elements located in introns and exons regulate the diminishment of intron/exon boundaries to prepare for exon ligation. Different types of exon fusion occur in one gene, generating diverse combinations of joined exons. Another approach to achieve exon ligation and rearrangement is via alternative splicing, a process commonly found in a variety of pathologies. Alternative splicing is regarded as a unique property of cancer cells and promote the activation of driver oncogenes, inactivation of tumor suppressor genes, and drug resistance. Hence, alternative splicing inhibition is highly applicable as a potential anticancer strategy.

Spliceosomes are complex macro-molecular assemblies that are comprise of small nuclear RNA (snRNA) and protein complexes. The correct assembly of spliceosomes is the prerequisite for mRNA alternative splicing, making them ideal intracellular targets for anti-tumor agents. Spliceosome inhibitors are known to have powerful anti-proliferative capabilities and target both actively dividing and quiescent cells. A group of potent inhibitors for eukaryotic mRNA splicing have been identified, including thailanstatin A, spliceostatin C and E7107, etc.

Schematic representation of spliceosome inhibitor actions. Spliceosome is the macromolecular machinery responsible for pre-mRNA splicing. Some small molecules interact with the spliceosome to promote its correct assembly. E7107, a spliceosome inhibitor, inhibits mRNA splicing by blocking the association of U2 snRNP with the intron branch point in pre-mRNAs. E7107 and other spliceosome inhibitors can also bind the core components in the SF3b complex, including SAP155, SA145, and SAP130, to preventing spliceosome assembly (Clin. Cancer Res, 2013).

Thailanstatin A

Thailanstatin A, a promising lead compound for drug discovery and development efforts, is derived from Thailandensis burkholderia MSMB43. It reveals low nanomolar to subnanomolar cytotoxicity against a variety of human cancer cell lines. The mechanism of action (MOA) of thailanstatin A is the inhibition of spliceosome assembly. Thailanstatin A binds firmly to the SF3b subunit of the U2 snRNA sub-complex, a crucial component of the spliceosome. Since the spliceosomes of cancer cells are more active and exhibits higher mutation rates than those of normal cells, this sub-cellular component is by far the most well-established anti-tumor target in novel drug discoveries.

Chemical structure of Thailanstatin A, a spliceosome inhibitor that binds to the SF3b subunit of the U2 snRNA sub-complex. This toxin has become a candidate for novel anticancer drug developments (J. Am. Chem. Soc., 2016).

Thailanstatin A-based ADCs

Thailanstatin A has been modified with the installation of a N-hydroxysuccinimide (NHS) ester and successfully conjugated to Trastuzumab via amine-based lysine conjugation to generate a virtually “linkerless” ADC. Trastuzumab thailanstatin has been tested in HER2 overexpression cell lines in vitro and showed accelerated splicing inhibition in N87 cells. Furthermore, Trastuzumab thailanstatin exhibits a remarkable potency in a gastric cancer xenograft model at doses as low as 1.5 mg/kg. In addition, compared to microtubule inhibitors such as maytansines or monomethyl auristatin E (MMAE), the thailanstatin A-based ADC is highly effective against a multi-drug resistant (MDR) tumor phenotype.

With our well-established “DrugLnk” organic synthesis platform, the experienced scientists here at Creative Biolabs is dedicated to help our client develop thailanstatin A-linker complexes using readily available or customized linkers for antibody conjugation 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.

References：

1. Dehm, S.M.; et al. Test-firing ammunition for spliceosome inhibition in cancer. Clin. Cancer Res. 2013, 19(22): 6064-6066.
2. Nicolaou, K.C.; et al. Total synthesis of thailanstatin A. J. Am. Chem. Soc. 2016, 138 (24): 7532–7535.
3. Puthenveetil, S.; et al. Natural product splicing inhibitors: a new class of antibody–drug conjugate (ADC) payloads. Bioconjugate Chem. 2016, 27(8): 1880-1888.

For Research Use Only. NOT FOR CLINICAL USE.