KL4‑219A is a more durable MYC degrader derived from structural optimization of KL2‑236, with its inactive diastereomer being KL4‑219B. KL4‑219A induces destabilization and degradation of MYC protein in a proteasome-dependent manner. KL4‑219A is applicable to the research of pancreatic cancer [1].
In Vitro, KL4-219A (50 μM; 0-24 h) induces potent, persistent proteasome-dependent MYC degradation in MYC-amplified PSN-1 pancreatic cancer cells, with sustained loss of MYC expression observed 24 h later[1]. KL4-219A-mediated MYC degradation in cancer cells is dependent on the proteasome; it exhibits whole-proteome selectivity for MYC degradation in cancer cells[1]. KL4-219A exhibits relatively selective cellular binding to MYC, which is evidenced by its ability to competitively inhibit the binding enrichment of KL2-236 to MYC in chemoproteomic analysis[1]. KL4-219A inhibits the transcriptional activity of MYC in HEK293T cells, and exhibits superior activity over its diastereomer KL4-219B[1]. KL4‑219A displayed an in vitro GSH half‑life of 19.3 minutes, which was shorter than that of the parent compound KL2‑236, and it exhibited sustained MYC degradation independent of warhead stability[1].
References:
[1]. Rosen HT, et al. Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC. Angewandte Chemie (International ed. in English). 2025 Nov 24;64(48):e202508518.
In Vitro, KL4-219A (50 μM; 0-24 h) induces potent, persistent proteasome-dependent MYC degradation in MYC-amplified PSN-1 pancreatic cancer cells, with sustained loss of MYC expression observed 24 h later[1]. KL4-219A-mediated MYC degradation in cancer cells is dependent on the proteasome; it exhibits whole-proteome selectivity for MYC degradation in cancer cells[1]. KL4-219A exhibits relatively selective cellular binding to MYC, which is evidenced by its ability to competitively inhibit the binding enrichment of KL2-236 to MYC in chemoproteomic analysis[1]. KL4-219A inhibits the transcriptional activity of MYC in HEK293T cells, and exhibits superior activity over its diastereomer KL4-219B[1]. KL4‑219A displayed an in vitro GSH half‑life of 19.3 minutes, which was shorter than that of the parent compound KL2‑236, and it exhibited sustained MYC degradation independent of warhead stability[1].
References:
[1]. Rosen HT, et al. Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC. Angewandte Chemie (International ed. in English). 2025 Nov 24;64(48):e202508518.