2. Academic Validation
  3. Synthesis and evaluation of KX-01 analogs with an exploration of linker attachment points for antibody-drug conjugates

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

  • Bioorg Med Chem Lett. 2025 Jan 27:120:130114. doi: 10.1016/j.bmcl.2025.130114.
Yeju Oh 1,  Da Eun An 2,  Jaebeom Park 2,  Byumseok Koh 1,  Kyung-Jin Cho 3,  Hongjun Jeon 4
Affiliations

Affiliations

  • 1 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114 Republic of Korea; Medicinal Chemistry & Pharmacology, University of Science & Technology, Daejeon 34113 Republic of Korea.
  • 2 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114 Republic of Korea.
  • 3 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114 Republic of Korea. Electronic address: kjcho@krict.re.kr.
  • 4 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114 Republic of Korea; Medicinal Chemistry & Pharmacology, University of Science & Technology, Daejeon 34113 Republic of Korea. Electronic address: hjeon@krict.re.kr.
PMID: 39880175 DOI: 10.1016/j.bmcl.2025.130114
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.

Keywords

Antibody-drug conjugate; Linker attachment; Microtubule-targeting agent; Payload.

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