KAT6A Inhibitor: 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 is a histone lysine acetyltransferase of the MYST family of acetyltransferases. It acylates both histone H3 and non-histone proteins, thereby playing multiple roles in regulation of transcription, various developmental processes, maintenance of hematopoietic and neural stem cells, regulation of hematopoietic cell differentiation, cell cycle progression and mitosis. Aberrant expression of KAT6A, and KAT6B leads to several developmental syndromes, and cancer. KAT6A is amplified as part of the 8p11 amplicon in 10-15% of breast cancer patients. Inhibition of KAT6A can decrease ERα expression via suppression of H3K23 acetylation, highlighting promise for this novel therapy in ER+ breast cancer patient population.
KAT6A overexpression opens chromatin to drive oncogene expression
ISM updated

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
The preclinical compound is a selective KAT6A inhibitor generated with the assistance of Insilico's AI platform Chemistry42. It demonstrates strong in vitro inhibitory activity and in vivo efficacy in ER+/HER2- breast cancer models especially demonstrated significant efficacy on tumor models derived from patients who relapsed on multiple prior lines of therapy. It also has favorable in vitro ADME properties and in vivo pharmacokinetic profile. Insilico has initiated Investigational New Drug (IND) enabling study of the compound to advance this internally developed program to the clinical stage.