Author: Tsavaschidis, Spyros ; Nguyen, Tuyen D.T. ; Fowlkes, Natalie W. ; Lulla, Amriti R. ; Hunt, Kelly K. ; Marshall, C. Gary ; Wang, Yan ; Pina, Marc A. ; Multani, Asha S. ; Chen, Mei-Kuang ; Sahin, Aysegul ; Keyomarsi, Khandan ; Wang, Fuchenchu ; Mastoraki, Sofia ; Karakas, Cansu ; Li, Mi ; Bui, Tuyen N.

AbstractCyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. The cleavage of full-length cyclin E (FL-cycE) to low–molecular weight isoforms (LMW-E) dramatically alters substrate specificity, promoting G1–S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. In this study, analysis of tumor samples of patients with TNBC revealed that coexpression of LMW-E and PKMYT1-catalyzed CDK1 phosphorylation predicted poor response to neoadjuvant chemotherapy. Compared with FL-cycE, LMW-E specifically upregulates PKMYT1 expression and protein stability, thereby increasing CDK1 phosphorylation. Inhibiting PKMYT1 with the selective inhibitor RP-6306 (lunresertib) elicited LMW-E–dependent antitumor effects, accelerating premature mitotic entry, inhibiting replication fork restart, and enhancing DNA damage, chromosomal breakage, apoptosis, and replication stress. Importantly, TNBC cell line xenografts expressing LMW-E showed greater sensitivity to RP-6306 than tumors with empty vector or FL-cycE. Furthermore, RP-6306 exerted tumor suppressive effects in LMW-E transgenic murine mammary tumors and patient-derived xenografts of LMW-E–high TNBC but not in the LMW-E null models examined in parallel. Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E–high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype.Significance: PKMYT1 upregulation and CDK1 phosphorylation in triple-negative breast cancer expressing low–molecular weight cyclin E leads to suboptimal responses to chemotherapy but sensitizes tumors to PKMYT1 inhibitors, proposing a personalized treatment strategy.

12 Sep 2024·Journal of Medicinal Chemistry

Structure-Based Drug Design of 2-Amino-[1,1′-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of CCNE1-Amplified Breast Cancer

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Author: Zhou, Ziqin ; Wan, Xuan ; Li, Yan ; Liu, Zhuoheng ; Xie, Hua ; Liu, Shuang ; Feng, Fang ; Lu, Xiaoyun ; Ding, Jian ; Fang, Yan ; Zhang, Zhi-Min ; Wang, Chaofan

CCNE1 amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for CCNE1 amplification holds promise for the treatment of CCNE1-amplified breast cancer. Herein, we discover a series of 2-amino-[1,1'-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design. The representative compound 8ma exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the CCNE1-amplified HCC1569 breast cancer cell line and showed synergistic cytotoxicity in combination with gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction of key binding interactions between the inhibitors and residues Asp251 and Tyr121 of PKMYT1 greatly enhanced the potency and selectivity of the compounds.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	CN	InSilico Medicine, Inc.	01 Dec 2023

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