8QDG

compound 1a bound KMT9 crystal structure

Summary for 8QDG

• Entry DOI: 10.2210/pdb8qdg/pdb
• Descriptor: Methyltransferase N6AMT1, Multifunctional methyltransferase subunit TRM112-like protein, (2~{S})-4-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-[(3~{S})-pyrrolidin-3-yl]amino]-2-azanyl-butanoic acid, ... (4 entities in total)
• Functional Keywords: protein transferase, gene regulation, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 36512.94

Authors

Sheng, W.,Eric, M.,Roland, S. (deposition date: 2023-08-29, release date: 2024-09-11, Last modification date: 2026-03-25)

Primary citation

Wang, S.,Klein, S.O.,Urban, S.,Staudt, M.,Barthes, N.P.F.,Willmann, D.,Bacher, J.,Sum, M.,Bauer, H.,Peng, L.,Rennar, G.A.,Gratzke, C.,Schule, K.M.,Zhang, L.,Einsle, O.,Greschik, H.,MacLeod, C.,Thomson, C.G.,Jung, M.,Metzger, E.,Schule, R.
Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity.
Nat Commun, 15:43-43, 2024

PubMed Abstract: Inhibition of epigenetic regulators by small molecules is an attractive strategy for cancer treatment. Recently, we characterised the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observation that the enzymatic activity was required for tumour cell proliferation identified KMT9 as a potential therapeutic target. Here, we report the development of a potent and selective KMT9 inhibitor (compound 4, KMI169) with cellular activity through structure-based drug design. KMI169 functions as a bi-substrate inhibitor targeting the SAM and substrate binding pockets of KMT9 and exhibits high potency, selectivity, and cellular target engagement. KMT9 inhibition selectively downregulates target genes involved in cell cycle regulation and impairs proliferation of tumours cells including castration- and enzalutamide-resistant prostate cancer cells. KMI169 represents a valuable tool to probe cellular KMT9 functions and paves the way for the development of clinical candidate inhibitors as therapeutic options to treat malignancies such as therapy-resistant prostate cancer.

PubMed: 38167811
DOI: 10.1038/s41467-023-44243-6

Experimental method

X-RAY DIFFRACTION (1.392 Å)