Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Translational Research, Drug development, Diseases, Treatment Considerations, Myeloid Malignancies
Targeting MLLT1/3 represents a novel therapeutic approach to blocking the SEC and inhibitors of MLLT1/3 histone reader function have been shown to have anti-cancer activity in a range of AML and ALL cell model systems. In this presentation we will describe the discovery of a first-in-class targeted protein degrader (TPD) of MLLT1/3 that has a markedly improved pharmacological profile vs MLLT1/3 inhibition and a differentiated profile vs menin-inhibition. This encompasses potent activity across a wide range of AML and ALL model systems including those that are resistant to menin-inhibitors.
Methods: Targeted degradation of MLLT1/3 was assessed using the Jess Simple Western system. MLLT target gene expression was measured by qPCR in leukemia cell lines. The anti-proliferative potential of MLLT1/3 targeted agents was assessed across a broad range of leukemic and normal cell lines and compared with menin inhibitors and other standard of care compounds using a cell viability readout. Combination studies were performed in leukemia cell lines with MLLT1/3 targeted agents, venetoclax and menin inhibitors. The clonogenic potential of MLLT1/3 targeted agents was determined using colony formation assays. Apoptosis was measured using caspase 3/7 readout. In vivo activity was assessed in a MV4-11 subcutaneous model.
Results: We have identified a novel and selective TPD of MLLT1/3, based on a highly selective YEATS domain binding small molecule inhibitor, that led to rapid and potent degradation of mouse and human MLLT1/3 with DC50 values <1nM. This compound blocked SEC mediated gene transcription of multiple oncogenes including MYC and MYB. In leukemic model cell systems, the MLLT1/3 TPD potently induced apoptosis or terminal differentiation, and blocked clonogenic potential of the cancer cells with minimal impact against non-cancer cells. In head-to-head studies the MLLT1/3 TPD provided markedly more potent and broader anti-cancer activity across a panel of AML and ALL cells than the MLLT1/3 inhibitor and a clinical menin-inhibitor. This included benefit in KMT2Ar and NPM1m driven leukemia cell lines, and in cell lines with other driver events not sensitive to menin-inhibition. Notably, the MLLT1/3 TPD was highly active against AML cells engineered to express clinically relevant drug-resistant menin-mutations. Furthermore, the MLLT1/3 TPD showed synergistic anti-cancer activity when combined with standard-of-care agents such as venetoclax and with menin inhibitors. In an in vivo MV4-11 xenograft model the MLLT1/3 TPD degraded MLLT1 protein, downregulated SEC target gene transcription and blocked tumour growth at well tolerated oral doses, with no evidence of hematological toxicity.
Conclusion: Targeting MLLT1/3 with a TPD is an attractive approach with potential as a single agent across a broad range of molecularly defined acute leukemias. Notably, marked activity in menin-resistant leukemic cell models was observed, supporting the potential to treat patients refractory to, or who progress on, menin-inhibitors: a high unmet clinical need. Finally, beneficial combinations with clinically relevant agents support the potential for a MLLT1/3 TPD to be used as part of early line standard-of-care treatment in AML and ALL.
Disclosures: Pollard: Grey Wolf Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Craggs: Dark Blue Therapeutics: Current Employment, Current holder of stock options in a privately-held company; e-therapeutics PLC: Ended employment in the past 24 months. Farnie: Dark Blue Therapeutics: Consultancy, Current equity holder in private company. Fawkes: Vertex: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; Dark Blue Therapeutics: Current Employment, Current holder of stock options in a privately-held company; Merck: Current equity holder in publicly-traded company; Thermo Fisher: Current equity holder in publicly-traded company; Eli Lilly and Co: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Astrazeneca: Current equity holder in publicly-traded company. Gross: Dark Blue Therapeutics: Current Employment, Current holder of stock options in a privately-held company; Nazare: Other: Spouse employed at Nazare. Harman: Dark Blue Theraputics: Current Employment, Current holder of stock options in a privately-held company. Llorca-Cardenosa: Dark Blue Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Major: Dark Blue Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Maloney: UCB: Current equity holder in publicly-traded company; Dark Blue Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Milne: Dark Blue Therapeutics: Consultancy, Other: T.A.M. is a paid consultant for and shareholder in Dark Blue Therapeutics Ltd.. Simpson: Dark Blue Therapeutics: Current Employment, Current holder of stock options in a privately-held company; Vertex: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months.
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