Discovery and Development of Dolastatin 10-Derived Antibody Drug Conjugate Anticancer Drugs.
Sheo B SinghPublished in: Journal of natural products (2022)
Dolastatin 10 is an extremely potent broad-spectrum antitubulin anticancer pentapeptide isolated from Dolabella auricularia . The two-dimensional structure was elucidated by NMR and mass spectrometric analyses. The absolute configuration was determined by a convergent total synthesis. SAR studies established that modifications at C- and N-terminals were tolerated for cytotoxic activity. Human clinical trials of dolastatin 10 and auristatin PE (a C-terminal analog) showed occasional signs of efficacy but failed due to lack of separation of toxicity and efficacy. Nanomolar cytotoxicity helped transition this class of pentapeptides to the next phase of development as antibody drug conjugates (ADCs) by reducing systemic toxicity. Four ADC drugs (Adcetris, Padcev, Polivy, and Blenrep) carrying monomethyl auristatin E (MMAE, vedotin) and monomethyl auristatin F (MMAF, mafodotin) payloads have been approved for treatment of a number of cancers expressing antibody-specific antigens. More than 36 ADCs carrying a variety of pentapeptide analogues are undergoing preclinical and clinical developments. They are being evaluated in more than 200 human trials. A comprehensive review of the discovery, total synthesis of dolastatin 10 and new amino acids, SAR studies of dolastatin 10 and auristatins, conjugations to antibodies, and preclinical and clinical development of ADCs have been presented.
Keyphrases
- endothelial cells
- clinical trial
- small molecule
- oxidative stress
- induced pluripotent stem cells
- high throughput
- magnetic resonance
- cancer therapy
- high resolution
- pluripotent stem cells
- dendritic cells
- case control
- magnetic resonance imaging
- computed tomography
- drug delivery
- anti inflammatory
- molecular docking
- hodgkin lymphoma
- drug induced
- study protocol
- smoking cessation
- oxide nanoparticles
- solid state