Discovery of Dolastatinol: A Synthetic Analog of Dolastatin 10 and Low Nanomolar Inhibitor of Tubulin Polymerization

Gutman, Hodaya; Bazylevich, Andrii; Prasad, Chandrashekhar; Dorfman, Ortal; Hesin, Arkadi; Marks, Vered; Patsenker, L. D.; Gellerman, Gary

doi:10.1021/acsmedchemlett.1c00432

Cited by 8 publications

(2 citation statements)

References 32 publications

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“…They reported simple analogues, such as ethyl ester (55), alkyl aniline (56), and free thiol (57) with cytotoxicities like MMAE (IC 50 0.66 nM, SKOV-3). Gutman et al (2021) 94 likewise synthesized a potent 4-hydroxymethyl analogue (dolastatinol, 58, IC 50 2.3 nM, BT474) of dolastatin 10, which could be used for linker attachment and conjugation of mAbs.…”

Section: Sar Of (22s)-valine (Val P2) Pettit Et Al (1995)mentioning

confidence: 99%

Discovery and Development of Dolastatin 10-Derived Antibody Drug Conjugate Anticancer Drugs

Singh

2022

J. Nat. Prod.

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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.

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Section: Sar Of (22s)-valine (Val P2) Pettit Et Al (1995)mentioning

confidence: 99%

Discovery and Development of Dolastatin 10-Derived Antibody Drug Conjugate Anticancer Drugs

Singh

2022

J. Nat. Prod.

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“…However, despite the benefits of microtubule-targeting drugs such as taxol and the vinca alkaloids in the clinic, the development of drug resistance and dose-limiting toxicities restrict their clinical efficacy [39]. Recently reported structurally diverse tubulin-targeting compounds with potent activities include the peptide dolastatinol 4 (Figure 2) [40] and the hydroquinoxalinone 5, binding at the colchicine site [41]. The bisindole sabizabulin 6 (ABI-231, Veru-111) is a potent, orally bioavailable tubulin inhibitor in clinical trials for metastatic castration-resistant prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones

et al. 2022

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The stilbene combretastatin A-4 (CA-4) is a potent microtubule-disrupting agent interacting at the colchicine-binding site of tubulin. In the present work, the synthesis, characterisation and mechanism of action of a series of 3-fluoro and 3,3-difluoro substituted β-lactams as analogues of the tubulin-targeting agent CA-4 are described. The synthesis was achieved by a convenient microwave-assisted Reformatsky reaction and is the first report of 3-fluoro and 3,3-difluoro β-lactams as CA-4 analogues. The β-lactam compounds 3-fluoro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxy phenyl)azetidin-2-one 32 and 3-fluoro-4-(3-fluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) 33 exhibited potent activity in MCF-7 human breast cancer cells with IC50 values of 0.075 µM and 0.095 µM, respectively, and demonstrated low toxicity in non-cancerous cells. Compound 32 also demonstrated significant antiproliferative activity at nanomolar concentrations in the triple-negative breast cancer cell line Hs578T (IC50 0.033 μM), together with potency in the invasive isogenic subclone Hs578Ts(i)8 (IC50 = 0.065 μM), while 33 was also effective in MDA-MB-231 cells (IC50 0.620 μM). Mechanistic studies demonstrated that 33 inhibited tubulin polymerisation, induced apoptosis in MCF-7 cells, and induced a downregulation in the expression of anti-apoptotic Bcl2 and survivin with corresponding upregulation in the expression of pro-apoptotic Bax. In silico studies indicated the interaction of the compounds with the colchicine-binding site, demonstrating the potential for further developing novel cancer therapeutics as microtubule-targeting agents.

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Synthesis and anticancer properties of novel dolastatin 10 analogs featuring five-membered heterocyclic rings with a linkable group at the C-terminus

Panja,

Sharma,

Mitra

et al. 2024

Bioorganic & Medicinal Chemistry

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Discovery of Dolastatinol: A Synthetic Analog of Dolastatin 10 and Low Nanomolar Inhibitor of Tubulin Polymerization

Cited by 8 publications

References 32 publications

Discovery and Development of Dolastatin 10-Derived Antibody Drug Conjugate Anticancer Drugs

Discovery and Development of Dolastatin 10-Derived Antibody Drug Conjugate Anticancer Drugs

Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones

Synthesis and anticancer properties of novel dolastatin 10 analogs featuring five-membered heterocyclic rings with a linkable group at the C-terminus

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