(S)-dHTC1

(S)-dHTC1 (compound 7) (1 nM-100 μM; 0.5-120 h) induces dose- and time-dependent ENL degradation in MV4;11 HiBiT-ENL cells, and retains degradation activity after prolonged exposure, with only a weak high-concentration hook effect; under the same conditions, (R)-dHTC1 shows essentially no ENL degradation activity^[1].
(S)-dHTC1 (1 nM-100 μM) induces varying degrees of dose-dependent ENL degradation in OCI-AML2, MOLM-13, HL-60, OCI-AML3, EOL1, and MV4;11 HiBiT-ENL cells, whereas (R)-dHTC1 is largely inactive^[1].
(S)-dHTC1 binds directly to the purified ENL YEATS domain, with a K_D of 49 nM determined by SPR, which is similar to the binding affinity of the inactive (R)-dHTC1 for ENL^[1].
(S)-dHTC1 (1 nM-100 μM; 3 h; 1 h pre-incubation with 1 μM MLN4924) binds intracellular ENL YEATS in OCI-AML2 cells with an EC₅₀ of 10.0 μM^[1].
(S)-dHTC1 binds weakly to purified CRBN^midi as an independent binary interaction, with a K_D of 63 μM as measured by SPR^[1].
(S)-dHTC1 (1 nM-100 μM; 2 h; followed by dBET6 500 nM for 1 h) does not significantly antagonize dBET6-induced BRD4 degradation in MV4;11-BRD4-HiBiT cells, supporting its weak intracellular binding to CRBN as a single agent^[1].
(S)-dHTC1 (1 nM-100 μM; ENL YEATS 3 μM) significantly enhances the CRBN FP competition signal in the presence of ENL YEATS, whereas it shows only a weak effect in the absence of ENL, indicating that its CRBN binding depends on the preformed ENL:(S)-dHTC1 complex^[1].
(S)-dHTC1 (1 μM) promotes the binding of CRBN-DDB1 to immobilized ENL YEATS and forms a ternary complex, whereas (R)-dHTC1 with the opposite configuration hardly induces this interaction^[1].
(S)-dHTC1 binds ENL with a K_D of 53 nM in the absence of CRBN-DDB1 and a K_D of 39 nM in the presence of CRBN-DDB1 (500 nM), indicating that ternary complex formation further stabilizes ENL binding^[1].
(S)-dHTC1 (1 nM-100 μM; CRBN-DDB1 500 nM) induces ENL-CRBN-DDB1 ternary complex formation in SPR experiments and exhibits a pronounced hook effect, whereas (R)-dHTC1 shows very weak ternary complex formation capacity^[1].
(S)-dHTC1 (1 nM-1 mM) induces proximity between ENL YEATS and CRBN-DDB1 in the TR-FRET assay and exhibits a hook effect, whereas (R)-dHTC1 shows very weak proximity-inducing activity^[1].
(S)-dHTC1 (1 nM-100 μM; 24 h) enhances the potency and depth of ENL degradation with increasing CRBN expression in MOLM-13 HiBiT-ENL cells with different CRBN overexpression levels, whereas (R)-dHTC1 remains largely inactive^[1].
(S)-dHTC1 (1 μM; 24 h) fails to effectively degrade ENL-R16A and ENL-E74A in MV4;11 ENL-TagBFP reporter cells, shows reduced degradation of ENL-K72A, while ENL-Q41A is more sensitive to it, confirming that the ENL-CRBN protein-protein interface is a key determinant of (S)-dHTC1 activity^[1].
(S)-dHTC1 (39.07, 78.13, 156, 312, 625 nM, 1.25, 2.5, 5, 10 μM; 12 days; fresh compound supplemented every 3 days) inhibits ENL-dependent MV4;11 cell growth in a stereoselective and CRBN-dependent manner, with minimal effect on ENL-independent HL-60 cells; CRBN loss confers resistance to (S)-dHTC1 in MV4;11 cells, and (R)-dHTC1 has essentially no effect on either cell line^[1].

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