Discovery of SY-14556, a highly potent and selective small molecule reactivator of p53 Y220C mutant with differentiated preclinical profile
Presenter: Yinghui Sun, PhD Session: Novel Antitumor Agents 2 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Hongjuan Li , Zhenbang Lou , Xiaopeng Li , Chang Lu , Shikang Cheng , Bo Li , Xianxing Shang , Xiaofeng Zhai , Yan Zhu , Hong Luo , Yinghui Sun Shouyao Holding (Beijing) Co., Ltd., Beijing, China
Abstract
As a key tumor suppressor, p53 binds to DNA and transcriptionally activates target genes to regulate cell-cycle arrest, DNA damage repair, apoptosis, and multiple other antiproliferative processes. TP53 is the most frequently mutated gene in human cancer, and Y220C is one hot-spot mutation occurring in approximately 1% of solid tumors. Pharmacologic stabilization and reactivation of the Y220C mutant to a wild-type-like conformation is a validated therapeutic strategy, as demonstrated by the clinical activity of PC14586 (rezatapopt). Here, we characterize SY-14556 as a highly potent and selective p53 Y220C reactivator. In biochemical assay, SY-14556 induced p53 Y220C DNA binding with an EC 50 50 50 20-100 nM) with >100-fold selectivity over p53-WT cells. Consistent with high-fidelity p53 pathway reactivation, SY-14556 also dose-dependently activated p53 target genes expression including p21 and MDM2, inducing cell cycle arrest and apoptosis. In vivo, SY-14556 demonstrated robust anti-tumor activity in several p53 Y220C-mutant cell line-derived xenograft (CDX) models. Furthermore, SY-14556 displayed favorable PK properties and tolerability in preclinical studies. In conclusion, SY-14556 is a best-in class p53-Y220C reactivator with robust preclinical efficacy and safety. These data support its advancement into clinical trials for p53 Y220C-mutant solid tumors.
Disclosure
H. Li, None.. Z. Lou, None.. X. Li, None.. C. Lu, None.. S. Cheng, None.. B. Li, None.. X. Shang, None.. X. Zhai, None.. Y. Zhu, None.. H. Luo, None.. Y. Sun, None.
Cited in
Control: 3520 · Presentation Id: 8830 · Meeting 21436