A first-in-class oral clinical candidate targeting MLLT1 and 3 degradation for the treatment of advanced AML and ALL including menin inhibitor resistant / refractory disease

Abstract

Abstract Background: MLLT-1 and 3 proteins are highly homologous histone readers that are constitutive regulators of the Super Elongation Complex (SEC), a key developmental transcription regulator. The SEC is hijacked by some solid cancers and acute leukemias, where it is directed to transcription start sites of major tumour drivers and oncogenes e.g. MYC, HOXA9, MEIS1 promoting rapid transcription. Furthermore, genetic studies have shown the SEC is a key dependency in acute leukemias. Targeting the SEC has been clinically validated with agents that target menin (a transcriptional coregulator identified in some but not all SECs) in late-stage KMT2Ar and mNPM1 acute leukemias. However, many patients are refractory to treatment and those that do respond often progress rapidly. Accordingly, a high unmet need remains. We have developed a first-in-class MLLT1 and 3 targeted protein degrader (MLLT-TPD) currently in IND enabling studies. This compound inhibits SEC-mediated gene transcription with potent and broad single agent activity across a panel of acute leukemic cell lines, including several refractory to menin inhibitors. The MLLT-TPD is highly effective in mouse models of AML and has ADME properties consistent with low oral doses in patients. Finally, the compound combines beneficially with a range of clinically relevant agents, supporting a strong potential as the backbone for combination therapy. Methods: Degradation of MLLT1 and 3 was assessed by JESS Simple Western or Western blotting. MLLT target gene expression was measured by qPCR. Viability was assessed across a broad range of leukemic and non-cancer cell lines by Cell-TiterGlo assays, along with terminal phenotype assessment e.g. differentiation and apoptosis. Combination studies were performed in viability assays with menin inhibitors and other standard of care (SOC) therapies e.g. venetoclax, azacitidine. MLLT-TPD selectivity was assessed by whole-cell proteomics. In vivo activity (PK/PD and efficacy) was assessed in the MV4-11 mouse xenograft model. Results: We have developed a novel first-in-class clinical candidate MLLT-TPD, that drives rapid and potent degradation of both mouse and human MLLT1 and 3 (4h DC50 <5nM) resulting in sustained downregulation of SEC-mediated gene transcription e.g. HOXA9, MYC, MYB. Mechanism of action studies confirm cereblon- and proteasome-mediated degradation with high selectivity for MLLT and no evidence of cereblon-neosubstrate degradation. The MLLT-TPD has a profound impact on cell viability (low nM activity) across a panel of AML and ALL cell lines, whilst sparing non-cancer cell lines. Several of the MLLT-TPD sensitive acute leukemia lines are refractory to menin inhibitors. Degradation of MLLT leads to reversal of the differentiation block that defines AML and induces apoptosis. Furthermore, MLLT-TPD shows synergistic anti-cancer activity when combined with SOC agents such as venetoclax or azacitidine and with a range of targeted agents including FLT3, IDH and menin inhibitors. In mouse models of AML, low oral doses of the MLLT-TPD lead to complete tumour regression with no evidence of hematological toxicity or body weight loss. These effects correlate with strong MLLT degradation and robust downregulation of SEC target genes in the tumors of mice treated with the compound. The clinical candidate MLLT-TPD has excellent ADME properties including good cross-species oral bioavailability, consistent with low oral doses in patients. Conclusion: We disclose the first-in-class MLLT targeted clinical candidate, which has a TPD mechanism of action. This compound has potent anti-cancer activity across a broad panel of acute leukemia cell lines, including those refractory to menin inhibitors, and in mouse models of AML, which supports a strong single agent opportunity in late-stage disease. Furthermore, synergistic activity with standard of care chemotherapy and a range of clinically relevant targeted agents, coupled with the compound's benign safety profile, support potential for our MLLT-TPD to become the backbone for combinations in early line treatment. Our data demonstrates that targeting MLLT1 and 3, the key regulators of the SEC, represents the best-in-class approach for disrupting SEC-driven oncogene addiction. IND-enabling studies are ongoing with first-in-human studies in relapsed / refractory acute leukemia (including in patients that progress on menin inhibitors) planned for early 2026.