MOZ inhibitors
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A series of novel and potent inhibitors of the histone acetyltransferase monocytic zinc finger leukaemia protein
MOZ (MYST3, KAT6A) with potential application in treating cancers
- Highly selective and potent (low nanomolar) small molecule inhibitors of the epigenetic drug target MOZ (KAT6A)
- Target genetically validated in a mouse model of B-cell lymphoma
- In vivo proof-of-concept studies underway
MOZ was originally identified in a recurrent chromosomal translocation, in an aggressive myeloid leukaemia, fusing the MOZ gene to CBP. Other blood cancers involving MOZ fusion proteins have a poor prognosis with a mean survival of less than 5 months. In addition, studies of copy number variations have shown that MOZ is located within the twelfth most commonly amplified genomic regions across all cancer types. Thus, inhibition of MOZ may provide a therapeutic benefit in a range of cancers.
Studies have been performed to genetically validate the targeting of MOZ in cancer. In Eµ-Myc-transgenic mice, a widely-used model to investigate MYC-driven B-cell lymphoma, the loss of just one allele of MOZ increased the median survival by 4-fold. In addition, MOZ+/- Eµ-Myc transgenic mice displayed a reduction in Bcell numbers, along with a compensatory increase in T-cell (CD4+, CD8+) numbers, in the periphery.
Further published work demonstrated that MOZ is required to maintain the proliferative capacity of B cell progenitors, even in the presence of MYC overexpression, by directly maintaining the transcriptional activity of genes required for normal B-cell development.1 Taken together, these studies provide a strong rationale for targeting MOZ in blood cancer.
From an initial hit identified through screening of 243,000 diverse small molecule compounds,2 researchers led by Prof. Jonathan Baell from Monash Institute of Pharmaceutical Sciences and Assoc. Prof. Tim Thomas from The Walter and Eliza Hall Institute, have developed a series of novel and potent MYST family inhibitors.
The Monash MYST family inhibitors have high affinity for MOZ (KAT6A) and MYST4 (KAT6B) and are selective, being at least 5- fold less active towards other MYST family members (Table 1). Compounds have been co-crystallised with MOZ and numerous crystal complexes have been obtained at high resolution (1.8A˚).
Compounds have demonstrated activity in vitro, inhibiting the growth of Eµ-Myc B-cells. In addition, treating mice with a MOZ inhibitor reduced B cell progenitor numbers without affecting total bone marrow cellularity. Thus, targeting MOZ is a promising therapeutic strategy, which offers the potential to extend survival in blood cancer and could be beneficial in a range of cancers.
Licensing
09/06/2016 00:00:00
AU2016277367
JA2017-563525
Others
Monash seeks a license partner to co-develop its advance lead series of MOZ inhibitors through preclinical development and nomination of a clinical candidate, to evaluation in clinical trials
2016-001
Australia
