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

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.

SUBMITTER: Hartmann RW 

PROVIDER: S-EPMC7756782 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature