MLLT-TPD

MLLT-TPD is a first-in-class oral targeted protein degrader (TPD) designed to selectively degrade MLLT1 and MLLT3, two homologous histone reader proteins critical to the Super Elongation Complex (SEC), a transcriptional regulator hijacked in various leukemias. It leverages a highly selective YEATS domain-binding small molecule inhibitor to achieve rapid and potent degradation (DC50 <1 nM) of both mouse and human MLLT1/3, blocking SEC-mediated transcription of oncogenes like MYC and MYB. In preclinical studies, it demonstrates superior anti-proliferative activity, apoptosis induction, and tumor growth inhibition in AML and ALL models—including KMT2A-rearranged (KMT2Ar), NPM1-mutated (NPM1m), and menin inhibitor-resistant cells—compared to MLLT1/3 inhibitors or menin inhibitors, with synergy alongside venetoclax and good tolerability in vivo.[2][4][9][11]