Synthesis and evaluation of KX-01 analogs with an exploration of linker attachment points for antibody-drug conjugates

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI:10.1016/j.bmcl.2025.130114

Yeju Oh , Da Eun An , Jaebeom Park , Byumseok Koh , Kyung-Jin Cho , Hongjun Jeon

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引用次数: 0

Abstract

KX-01 (tirbanibulin, Klisyri®) is a recently FDA-approved drug for treating actinic keratosis, with a distinct dual mechanism of action combining microtubule disruption and non-ATP-competitive Src inhibition. This unique mechanism and novel chemotype highlight KX-01′s potential as a payload for antibody-drug conjugates. In this study, we synthesized and evaluated KX-01 derivatives to enhance anticancer potency and explore functional groups suitable for antibody conjugation. Notably, replacing the morpholine group with an N-benzoylpiperazine scaffold resulted in an analog with significantly improved in vitro antiproliferative activity, attributed to enhanced microtubule disruption and Src inhibition. Furthermore, introducing a phenol or aniline functionality as a common linker attachment point preserved substantial cytotoxicity. These results suggest the potential of KX-01 derivatives for future use as ADC payloads.

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KX-01类似物的合成与评价及抗体-药物偶联物的连接点探索。

KX-01 （tirbanibulin, Klisyri®）是fda最近批准的用于治疗光化性角化病的药物，具有独特的双重作用机制，结合微管破坏和非atp竞争性Src抑制。这种独特的机制和新的化学型突出了KX-01作为抗体-药物偶联物有效载荷的潜力。在本研究中，我们合成并评估了KX-01衍生物，以增强其抗癌能力，并探索适合抗体偶联的官能团。值得注意的是，用n -苯甲酰基哌嗪支架取代啉基团导致类似物在体外抗增殖活性显著提高，这归因于增强的微管破坏和Src抑制。此外，引入苯酚或苯胺功能作为共同的连接体附着点保留了大量的细胞毒性。这些结果表明KX-01衍生物在未来用作ADC有效载荷的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.