TDI-11055 (TDI 11055) is a potent, selective and orally bioavailable inhibitor of the acyl-lysine reader ENL/AF9 YEATS domain with IC50 of 0.05 and 0.07 uM, respectively.
TDI-11055 shows no inhibition of the YEATS domains of GAS41 and YEATS2 (IC50 > 100 μM), the other two YEATS domain-containing proteins.
TDI-11055 shows direct binding affinity to the ENL YEATS domain with Kd of 119 nM in isothermal titration calorimetry (ITC) assays.
TDI-11055 binds to and stabilizes endogenously expressed ENL but not GAS41 or YEATS2 in cells, binds directly to the acyl-binding site in ENL and engages with key acyl-recognizing residues.
TDI-11055 treatment led to a substantial displacement of ENL from target genes, including well-established leukemogenic genes in AML such as MYC and the HOXA cluster, TDI-11055 is a validated chemical tool for efficiently and specifically perturbing the chromatin reader function of ENL in living cells.
TDI-11055 inhibits the growth of MLL-r and NPM1-mutated leukemia cells in vitro (MV4;11 cell viability IC50=0.27 uM), decreases the expression of several key oncogenes in AML, including MYC, HOXA9/10, and MYB.
TDI-11055 impairs the clonogenic potential and induces differentiation of MLL-r and NPM1-mutated primary AML patient samples, blocks disease progression in models of MLL-r leukemia.