Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Epigenetic regulators are attractive targets for cancer therapy.
• Lysine methyltransferase 9 (KMT9) plays a role in prostate, lung, and colon cancer proliferation.
• KMT9 enzymatic activity is crucial for tumor cell growth, identifying it as a therapeutic target.

Purpose of the Study:

• To develop a potent and selective small molecule inhibitor of KMT9.
• To characterize the inhibitor's mechanism of action and cellular activity.
• To evaluate the inhibitor's potential in treating therapy-resistant cancers.

Main Methods:

• Structure-based drug design was employed to develop the KMT9 inhibitor.
• The inhibitor, KMI169 (compound 4), was characterized for potency, selectivity, and cellular target engagement.
• KMT9's role in regulating target genes involved in cell cycle and tumor proliferation was assessed.

Main Results:

• A potent and selective KMT9 inhibitor, KMI169, was successfully developed.
• KMI169 acts as a bi-substrate inhibitor, targeting both SAM and substrate binding pockets.
• KMT9 inhibition selectively downregulated cell cycle genes and impaired proliferation in various cancer cells, including resistant prostate cancer.

Conclusions:

• KMI169 is a valuable tool for studying KMT9 function in cellular contexts.
• The development of KMI169 paves the way for clinical candidate inhibitors for malignancies.
• Targeting KMT9 offers a potential therapeutic strategy for therapy-resistant cancers, particularly prostate cancer.