Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing

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Abstract

Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour (“bystander killing”). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz-protected azastatin methyl ester (0.13–3.0 nM) inhibited proliferation more potently than MMAE (0.47–6.5 nM), removal of the Cbz-group yielded dramatically increased IC50-values (9.8–170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next-generation ADC development.

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Hartmann, R. W., Fahrner, R., Shevshenko, D., Fyrknäs, M., Larsson, R., Lehmann, F., & Odell, L. R. (2020). Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing. ChemMedChem, 15(24), 2500–2512. https://doi.org/10.1002/cmdc.202000497

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