A Small Molecule KAT6 Inhibitor as a Potential Treatment of ER+ HER2- Breast Cancer (Entering IND)
Assays Completed
Owned and Available for Licensing
In vivo efficacy studies
In vivo efficacy studies
with single agent
In vivo PK-PD
In vivo PK studies
In vitro ADMET studies
In vitro cell-based
Toxicology studies
Target Rationale
KAT6A, a member of the Moz-Ybf2/Sas3-Sas2-Tip60 ("MYST") family of histone acetyltransferase ("HAT"), catalyzes the acetylation of lysine residues on histones and non-histone proteins. Molecular dysregulation of KAT6A has been observed in several cancers, including amplifications in breast, lung, and ovarian cancers.

In addition, KAT6A is amplified in 10-15% of the breast cancer patient population and overexpression of KAT6A correlates with worse clinical outcome in patients with ER+/HER2- breast cancer. Thus, inhibition of KAT6A is able to block ERα at transcriptional level, which highlights promise for this novel therapy for ER+/HER2- breast cancer.

Insilico Medicine KAT6A Inhibitor Summary – IND-Enabling
Effective as mono-therapy for refractory ER+/HER2- BC
  • Potent anti-proliferation activity in ER+/Her2- breast cancer cell lines
  • Strong in vivo anti-tumor efficacy as mono-therapy with good tolerance in ER+ breast cancer CDX model
  • Lower efficacious dose in ER+/HER2- BC PDX model resistant to multiple chemo- and endocrine-therapies
Promising drug-ability as oral single/combo agent
  • Decent in vitro ADME profiles
  • Promising PK profiles across different preclinical animal species: low CL, high F and
    high AUC
  • Low DDI risk
safety margin

  • Promising MOS in in vivo toxicological studies
  • Excellent in vitro safety profiles
  • High selectivity over other histone acetyltransferases
Potentially broader indication scope

  • Strong in vitro and in vivo anti-tumor effects in multiple liquid tumor models

Breast cancer has exceeded lung cancer as the most diagnosed cancer and the fifth cause of cancer deaths worldwide in 2020. ER+/HER2- patients are the major population and endocrine therapy in combo with CDK4/6 inhibitors is the standard treatment for this population with advanced or metastatic disease. However, the overall response rate is less than 50%, indicating a huge unmet medical need in this area.

Molecular dysregulation of KAT6A, including amplification and fusion, has been reported in many cancers. In breast cancer, KAT6A is amplified as part of 8p11 amplicon in about 10-15% of the population and functions as an epigenetic modulator of expression level of estrogen receptor (ER). Therefore, targeting KAT6A will be a promising therapy for ER+/HER2- breast cancer patients. As KAT6A regulates ER expression at transcription level, it has the potential to overcome resistance to endocrine therapies due to mutation or ligand-independent constitutive activation of ER.

Project Status – IND-Enabling Drug Candidate
A novel oral small molecule KAT6-selective inhibitor with comparable potency against both KAT6A and its close paralog KAT6B. The preclinical studies showed its potent inhibition against KAT6A and promising safety and efficacy profiles. We have initiated IND-enabling studies and expect to file an IND submission in the first half of 2024.

Discovered by leveraging our Pharma.AI platform. By using our Generative Chemistry application, small molecules with potent inhibitory effect against KAT6A were selected and the molecule was nominated as a preclinical candidate for the treatment of ER+/HER2- breast cancer.