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Pfizer Oncology
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The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

KAT6 Inhibitor

Geo Regions

KAT6 Inhibitor

PF-07248144 is an investigational compound. Its safety and efficacy have not been established.

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Overview + Rationale

  • Functionally active fusions of Lysine Acetyltransferase 6A (KAT6A) with CBP1, p3002 or TIF23 have been described in AML and the resulting aberrant acetylation might contribute to the process of leukaemogenesis
  • KAT6A contributes to the inhibition of cell senescence, and therefore to tumor cell immortality
  • Inhibition of histone acetyltransferases KAT6A/B was shown to induce senescence and to arrest tumor growth in mouse embryonic fibroblasts 
  • Loss of one allele of KAT6A was shown to extend the median survival of mice with MYC-induced lymphoma from 105 to 413 days 
  • PF-07248144 is a small molecule inhibitor of KAT6A

Mechanism of Action

  • As part of the bromodomain- and PHD finger-containing protein 1 (BRPF1) complex, KAT6A acetylates lysine residue 23 on histone H3* 
  • H3K23 acetylation leads to a relaxed chromatin enabling gene transcription • While acetylation by KAT6A potentially affects large parts of the DNA, certain transcription factors, as well as pre-existing epigenetic marks, were shown to recruit the BRPF1 complex for a more localized activity

Inhibition

Stage of Development

Breast
HR+/HER2- Metastatic Breast Cancer
Phase 1 Monotherapy and Combination
GU
Prostate Cancer
Phase 1 Monotherapy and Combination
Lung
Non-Small Cell Lung Cancer (NSCLC)
Phase 1 Monotherapy
This information is current as of October 30th 2024.

* other lysine residues on H3 have also been reported as KAT6a acetylation targets

REFERENCES:  Borrow et al., 1996. Nat Genet 14:33-41; Chaffanet et al., 2000. Gens Chromosom Cancer  28: 138-144; Carapeti et al., 1998. Blood 91:3127-3133; Sheik et al.,2015. Oncogene 34, 5807–5820; Baell et al., 2018 Nature 560: 253-257; Sheikh et al., 2015. Blood 125: 1910-1921; Yang, 2016. Biochim Biophys Acta 1853: 1818-1826; Carlson & Glass, 2014. J Cell Physiol 229: 1571-1574; Huang et al. 2016. Mol Cell Biol 36:1900-1907; Mukohara, T., Park, Y.H., Sommerhalder, D. et al. Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial. Nat Med 30, 2242–2250 (2024). https://doi.org/10.1038/s41591-024-03060-0;; ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04606446.  Accessed October 22, 2024.