DOT1L PROBES

摘要

The present invention relates to compound that bind Histone H3-lysine79 (H3K79) methyl transferase (DOTIL). The disclosed compounds are useful as for assessing the activity of DOTIL and for identifying inhibitors of DOTIL. Described herein are probes useful for both assessing the activity of DOTIL and identifying inhibitors of DOTIL. These probes can be used in various assays, including Amplified Luminescent Proximity Homogeneous Assays (“ALPHA” assays), Differential Scanning Fluorimetry (DFS) Assay, and Fluorescence Polarization (FP) assays used for high-throughput screening (HTS) for small molecule drug discovery. The compounds can also be used as a pull down agent for target identification.

主权项

1. A probe, comprising a compound having formula (I): wherein:
X is N or C—R5;Y is O or S;R1 is hydrogen or C1-3 alkyl;R2 is hydrogen, C1-3 alkyl, or R6;R3 is hydrogen, C1-6 alkyl, or R6;R4 is C1-8 alkyl, or N(R6)(R7), provided that one of R2, R3, and R4 is, or includes, R6;R5 is hydrogen, halo, C1-6 alkyl, or C1-6 haloalkyl;R6 is Z—R8;Z is a divalent group consisting of any 1, 2, 3, 4, or 5 of the following independently selected moieties:
(i) C1-30 alkylene;(ii) heteroalkylene that spans from 3-20 atoms in length wherein from 1-8 of the atoms in the span are heteroatomic groups that are each independently selected from N, NH, N—C1-C6 alkyl, O, and S, provided that there is at least one carbon atom between the occurrence of any two heteroatomic groups;(iii) polyheteroalkylene chain that spans from 21-100 atoms in length wherein from 1-50 of the atoms in the span are heteroatomic groups that are each independently selected from N, NH, N—C1-C6 alkyl, O, and S, provided that there is at least one carbon atom between the occurrence of any two heteroatomic groups;(iv) C2-30 alkenylene chain; and(v) —OC(═O)—, —C(═O)O—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)NH—, —NHC(═S)NH—, —OC(═O)NH—, and —NHC(═O)O—;R7 is hydrogen or C1-3 alkyl; andR8 is an affinity tag or a fluorescent label.