Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy

Chowdari, Naidu S.; Pan, Chin Chen; Rao, Chetana; Langley, David R.; Sivaprakasam, Prasanna; Sufi, Bilal A.; Derwin, Daniel; Wang, Yichong; Kwok, Eilene; Passmore, David; Rangan, Vangipuram S.; Deshpande, Shrikant; Cardarelli, Pina M.; Vite, Gregory D.; Gangwar, Sanjeev

doi:10.1016/j.bmcl.2018.12.021

Cited by 24 publications

(31 citation statements)

References 26 publications

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“…Thus, ADCs have emerged as a promising anticancer therapy recently by combining a tumor targeting antibody and highly cytotoxic payload via a chemical The Chowdari group synthesized two UCM analogues (140 and 141) with an NH 2 group at the C8 position. 104 Both compounds exhibited much higher potency than MMAE, the payload used in the FDA approved ADC Adcetris. Because 141 has better chemical reactivity, it was chosen to append different linkers.…”

Section: Preclinical Developments Of Afebased Adcsmentioning

confidence: 99%

“…In contrast, the 146conjugated ADCs were not active on either cell lines, probably due to the non-cleavable nature of the linker. 104 Poudel and co-workers addressed the mouse serum instability issue of the UCM linker-payload by modifying different parts of the linker and payload. Ultimately, a linker-payload (144) containing valine-citrulline with a self-immolating mamide p-aminobenzyl carbamate (MA-PABC) was found to be resistant to serum hydrolysis but sensitive to intracellular protease cleavage (Fig.…”

Section: Reviewmentioning

confidence: 99%

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Anthraquinone-fused enediynes: discovery, biosynthesis and development

Yan

2022

Nat. Prod. Rep.

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Section: Preclinical Developments Of Afebased Adcsmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Anthraquinone-fused enediynes: discovery, biosynthesis and development

Yan

2022

Nat. Prod. Rep.

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“…In addition to all of the above-mentioned payloads, other molecules available also act as DNA-damaging agents for incorporation into newly emerging ADCs. Among these compounds, particular mention should be given to iSGD-1882 (DNA minor groove cross-linker derived from PBD dimers), centanamycin (binds to DNA and alkylates or intercalates into DNA), PNU-159682 (an anthracycline metabolite) [ 69 ], and uncialamycin (an enediyne natural product isolated from Streptomyces uncialis) [ 70 ], all active on different cancer cell lines, and finally indolinobenzodiazepine dimers (IGNs) bind to the DNA minor groove leading to DNA cross-linking [ 71 ].…”

Section: Basic Characteristics Of the Conjugatementioning

confidence: 99%

Antibody-Drug Conjugates: The New Frontier of Chemotherapy

Ponziani

Vittorio²,

Pitari

et al. 2020

IJMS

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In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents to be used as one of the tools in personalized cancer medicine. ADCs are comprised of a drug with cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. By providing a selective targeting mechanism for cytotoxic drugs, ADCs improve the therapeutic index in clinical practice. In this review, the chemistry of ADC linker conjugation together with strategies adopted to improve antibody tolerability (by reducing antigenicity) are examined, with particular attention to ADCs approved by the regulatory agencies (the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) for treating cancer patients. Recent developments in engineering Immunoglobulin (Ig) genes and antibody humanization have greatly reduced some of the problems of the first generation of ADCs, beset by problems, such as random coupling of the payload and immunogenicity of the antibody. ADC development and clinical use is a fast, evolving area, and will likely prove an important modality for the treatment of cancer in the near future.

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“…Besides the abovementioned payloads, other molecules, which can be used as a DNA‐damaging agent in ADC synthesis, include SGD‐1882 (a cytotoxic DNA minor groove cross‐linking derivative of PBD dimers which is not an MDR1 substrate) (Kim & Kim, ), centanamycin (an indolecarboxamide synthesized as a less toxic analog of CC‐1065 and duocarmycin which binds to DNA and alkylates or intercalates into the DNA) (Beck et al, ; Kim & Kim, ), PNU‐159682 (a highly potent metabolite of the anthracyclines which shows three folds more cytotoxicity compared with doxorubicin) (Yu et al, ), and uncialamycin (an enediyne natural product isolated from the Streptomyces uncialis ) (Chowdari et al, ), all showing acceptable potency against a broad range of cancer cell lines. Indolinobenzodiazepine dimers, also known as IGNs, are an indolino‐benzodiazepine dimer consisting of a mono‐imine moiety, representing a novel set of cytotoxic agents with highly potent activity in vitro (an IC50 value of low pM) against a variety of cancer cells.…”

Section: Cytotoxic Payloads Used In Adc Artitecturesmentioning

confidence: 99%

Potential drugs used in the antibody–drug conjugate (ADC) architecture for cancer therapy

Yaghoubi

Karimi

Lotfinia

et al. 2019

Journal Cellular Physiology

106

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Cytotoxic small-molecule drugs have a major influence on the fate of antibody-drug conjugates (ADCs). An ideal cytotoxic agent should be highly potent, remain stable while linked to ADCs, kill the targeted tumor cell upon internalization and release from the ADCs, and maintain its activity in multidrug-resistant tumor cells. Lessons learned from successful and failed experiences in ADC development resulted in remarkable progress in the discovery and development of novel highly potent small molecules. A better understanding of such small-molecule drugs is important for development of effective ADCs. The present review discusses requirements making a payload appropriate for antitumor ADCs and focuses on the main characteristics of commonly-used cytotoxic payloads that showed acceptable results in clinical trials. In addition, the present study represents emerging trends and recent advances of payloads used in ADCs currently under clinical trials. K E Y W O R D S antibody-drug Conjugate (ADC), auristatin, calicheamicin, cytotoxic small molecules, maytansine, payloads, warheads

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Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy

Cited by 24 publications

References 26 publications

Anthraquinone-fused enediynes: discovery, biosynthesis and development

Anthraquinone-fused enediynes: discovery, biosynthesis and development

Antibody-Drug Conjugates: The New Frontier of Chemotherapy

Potential drugs used in the antibody–drug conjugate (ADC) architecture for cancer therapy

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