Evaluation of PNU-159682 antibody drug conjugates (ADCs),Bioorganic & Medicinal Chemistry Letters

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Evaluation of PNU-159682 antibody drug conjugates (ADCs)
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-10-28 , DOI: 10.1016/j.bmcl.2020.127640
Dane Holte ₁ , Joseph P Lyssikatos ₂ , Amanda M Valdiosera ₃ , Zachary Swinney ₄ , Vikram Sisodiya ₅ , Joseph Sandoval ₆ , Christina Lee ₇ , Monette A Aujay ₂ , Robert B Tchelepi ₈ , Omar M Hamdy ₉ , Christine Gu ₁₀ , Baiwei Lin ₁₁ , Hetal Sarvaiya ₇ , Marybeth A Pysz ₇ , Amy Laysang ₇ , Samuel Williams ₁₂ , Dong Jun Lee ₁₃ , Magda K Holda ₁₄ , James W Purcell ₇ , Julia Gavrilyuk ₇

Affiliation

AbbVie Chemical Development & Manufacturing, 995 East Arques Avenue, Sunnyvale, CA 94085, USA.
Enliven Therapeutics, 6200 Lookout Road, First Floor, Boulder, CO 80301, USA.
Parvus Therapeutics, 800 Dubuque Avenue, South San Francisco, CA 94080, USA.
Mantra Bio, 455 Mission Bay Boulevard, South San Francisco, CA 94158, USA.
Denali Therapeutics, 161 Oyster Point Bloulevard, South San Francisco, CA 94080, USA.
Fate Therapeutics, 3535 General Atomics Court, Suite 200, San Diego 92121, USA.
AbbVie Research & Development, 400 East Jamie Court, South San Francisco, CA 94080, USA.
Bolt Biotherapeutics, 640 Galveston Drive, Redwood City, CA 94063, USA.
Applied Molecular Transport, 1 Tower Place, Suite 850, South San Francisco, CA 94080, USA.
AbbVie Research & Development, 400 East Jamie Court, South San Francisco, CA 94080, USA; AbbVie Research & Development, 995 East Arques Avenue, Sunnyvale, CA 94085, USA.
Maze Therapeutics, 131 Oyster Point Blvd, Suite 200, South San Francisco, CA 94080, USA.
ArsenalBio, Inc. 2 Tower Place, South San Francisco, CA 94080, USA.
AbbVie Research & Development, 995 East Arques Avenue, Sunnyvale, CA 94085, USA.
AbbVie Research & Development, 1500 Seaport Blvd, Redwood City, CA 94063, USA.

PNU-159682 is a highly potent secondary metabolite of nemorubicin belonging to the anthracycline class of natural products. Due to its extremely high potency and only partially understood mechanism of action, it was deemed an interesting starting point for the development of a new suite of linker drugs for antibody drug conjugates (ADCs). Structure activity relationships were explored on the small molecule which led to six linker drugs being developed for conjugation to antibodies. Herein we describe the synthesis of novel PNU-159682 derivatives and the subsequent linker drugs as well as the corresponding biological evaluations of the small molecules and ADCs.

中文翻译：

PNU-159682抗体药物偶联物（ADC）的评估

PNU-159682是新霉素的高效次级代谢产物，属于天然蒽环类药物。由于其极高的效力和仅部分了解的作用机理，因此被认为是开发用于抗体药物偶联物（ADC）的新的连接剂套件的有趣起点。在小分子上探索了结构活性关系，这导致开发出六种用于与抗体缀合的接头药物。在这里，我们描述了新型PNU-159682衍生物的合成以及随后的接头药物以及小分子和ADC的相应生物学评估。

更新日期：2020-11-02

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