The OTAVA G9a Targeted Library comprises 561 carefully curated small molecules aimed at modulating the activity of histone methyltransferase G9a (EHMT2)—a master regulator of transcriptional repression through histone H3 lysine 9 (H3K9) methylation. This collection provides a powerful resource for researchers exploring epigenetics-driven mechanisms in cancer, neurodegeneration, inflammation, and stem cell reprogramming.

Why Target G9a (EHMT2)?

G9a, or EHMT2, is a SET domain-containing lysine methyltransferase that primarily catalyzes mono- and dimethylation of H3K9, a key repressive histone mark. Overexpression or aberrant activity of G9a is implicated in:

• Cancer: Promotes proliferation and EMT, suppresses tumor suppressor genes
• Neurodegenerative diseases: Affects synaptic plasticity, neurogenesis, and neuronal gene regulation
• Inflammatory disorders: Alters cytokine signaling and immune cell differentiation
• Developmental epigenetics: Regulates imprinting and chromatin structure

Given its central role in epigenetic gene silencing, G9a is a validated drug target in multiple therapeutic areas.

Library Design Highlights

▶ Scaffold-Based and SAR-Informed

The library is constructed around the 2,4-diamino-7-aminoalkoxyquinazoline scaffold—originally developed by Liu et al. (2010)—recognized for its potent and selective inhibition of G9a and GLP.

• IC₅₀ values as low as 6–9 nM for G9a and 15–23 nM for GLP
• Validated binding via X-ray crystallography
• Incorporates known active pharmacophores: basic nitrogen atoms, H-bond donors, and planar aromatics

▶ Structure- and Ligand-Based Selection

Using advanced cheminformatics, including:

• 3D molecular docking
• Pharmacophore modeling
• Structure–activity relationship (SAR) data mining
• Targeted chemical diversity sampling

These approaches ensure maintenance of critical interactions (e.g., with the lysine-binding channel) while exploring novel analogues and isosteric replacements.

▶ Dual Inhibition Potential

Several compounds are designed to potentially target both G9a and complementary epigenetic enzymes, such as HDACs or DNMT1, expanding the therapeutic relevance through synergistic epigenetic modulation.

Applications of the Library

The OTAVA G9a Targeted Library supports cutting-edge research in:

• Cancer epigenetics
  Inhibitors that restore tumor suppressor expression and enhance chemosensitivity
• Neuroepigenetics
  Tools for probing gene silencing in neurodegenerative and psychiatric disorders
• Immuno-oncology
  Epigenetic priming of immune responses via checkpoint modulation
• Stem cell biology and reprogramming
  Epigenetic unlocking of pluripotency via H3K9me2 modulation

Chemical and Biological Diversity

Contact us today to discuss library access, customization, and collaborative screening strategies tailored to your research needs.

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Key References

These foundational and recent studies form the scientific basis for our library's design—guiding the selection of proven molecular scaffolds, optimizing interactions with the G9a target, and ensuring strong biological relevance across therapeutic areas.

Design and Scaffold Validation

• Liu, F., Chen, X., Allali-Hassani, A., Quinn, A. M., Wigle, T. J., Wasney, G. A., Dong, A., Barsyte-Lovejoy, D., Senisterra, G., Chau, I., Siarheyeva, A., Tempel, W., Sankaran, B., Liu, J., Hai, Y., Grimshaw, S., Vedadi, M., & Jin, J. (2010). Protein lysine methyltransferase G9a inhibitors: Design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines. Journal of Medicinal Chemistry, 53(15), 5844–5857. https://doi.org/10.1021/jm100478y
  ▶ First study characterizing the quinazoline scaffold with potent, selective G9a inhibition.
• He, H., Li, X., Su, F., Jin, H., Zhang, J., & Wang, Y. (2024). Current and emerging approaches targeting G9a for the treatment of various diseases. Journal of Medicinal Chemistry. Advance online publication. https://doi.org/10.1021/acs.jmedchem.4c02781
  ▶ Review of G9a-targeting strategies and their relevance to cancer, neurodegeneration, and beyond.

Structure-Based and SAR-Guided Design

• Feng, Z., Yang, C., Zhang, Y., Li, H., Fang, W., Wang, J., Nie, Y., Wang, C.-Y., Liu, Z., Jiang, Z., Wang, J., & Wang, Y. (2023). Structure-based design and characterization of highly potent and selective covalent inhibitors targeting the lysine methyltransferases G9a/GLP. Journal of Medicinal Chemistry, 66(20), 14101–14116. https://doi.org/10.1021/acs.jmedchem.3c00411
  ▶ Describes covalent G9a/GLP inhibitors with high selectivity and nanomolar potency.
• Charles, M. R. C., Dhayalan, A., Hsieh, H.-P., & Coumar, M. S. (2019). Insights for the design of protein lysine methyltransferase G9a inhibitors. Future Medicinal Chemistry, 11(5), 475–495. https://doi.org/10.4155/FMC-2018-0396
  ▶ Provides medicinal chemistry insights for scaffold optimization and SAR trends.

Epigenetic Crosstalk and Dual Inhibition

• San José-Enériz, E., Agirre, X., Rabal, O., Vilas-Zornoza, A., Sanchez-Arias, J. A., Miranda, E., Ugarte, A., Roa, S., Paiva, B., Estella-Hermoso de Mendoza, A., Alvarez, R. M., Casares, N., Segura, V., Martín-Subero, J. I., Ogi, F.-X., Soule, P., Santiveri, C. M., Campos-Olivas, R., Castellano, G., … Prosper, F. (2017). Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies. Nature Communications, 8, Article 15424. https://doi.org/10.1038/ncomms15424
  ▶ This study reports the development of CM-272, a novel reversible dual inhibitor targeting both G9a and DNA methyltransferases (DNMTs), demonstrating significant anti-tumor activity in hematological malignancies.

Chemical Space Exploration and Cheminformatics

• Cedillo-González, R., & Medina-Franco, J. L. (2023). Diversity and chemical space characterization of inhibitors of the epigenetic target G9a: A chemoinformatics approach. ACS Omega, 8(45), 41690–41703. https://doi.org/10.1021/acsomega.3c04566
  ▶ Maps G9a inhibitor diversity using cheminformatics tools to identify novel chemotypes.

Biological Validation and Mechanistic Studies

• Zhang, K., Wang, J., Yang, L., Yuan, Y.-C., Tong, T., Wu, J., Yun, X., Bonner, M., Pangeni, R. P., Liu, Z., Yuchi, T., Kim, J. Y., & Raz, D. J. (2018). Targeting histone methyltransferase G9a inhibits growth and Wnt signaling pathway by epigenetically regulating HP1α and APC2 gene expression in non-small cell lung cancer. Molecular Cancer, 17, Article 153. https://doi.org/10.1186/s12943-018-0896-8
  ▶ Validates G9a as a therapeutic target in NSCLC by linking H3K9 methylation to Wnt signaling.