MT1

Bivalent inhibitor of BRD2, BRD4, BRD3, BRDT

Structure

Information

  • BRD2
  • BRD4
  • BRD3
  • BRDT
  • Bivalent inhibitor
  • 0.1-100 nM

In Vitro Validations

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): MT1 compound showed picomolar displacement of phage expressing: BRD2(1): 160 pM; BRD2(1,2): 24 pM; BRD2(2): 33 pM; BRD3(1):59 pM; BRD3(1,2): 12 pM; BRD3(2): 70 pM; BRD4(1): 99 pM; BRD4(1,2): 87 pM; BRD4(2): 53 pM; BRD4(full-length,short-iso.): 62 pM; BRDT(1): 560 pM; BRDT(1,2): 76 pM; BRDT(2): 86 pM; These dramatic increases in activity were confirmed to be selective for the BET family using a panel of 40 phage-displayed bromodomains (BROMOscan, DiscoverX). MT1 did not show significant binding to non-BET bromodomains at higher concentrations (IC50 = 1.8 μM for GCN5L2, 6.4 μM for CBP , 8.6 μM for EP300 and >10 μM for others: ATAD2A ATAD2B BAZ2A BAZ2B BRD1 BRD7 BRD8(1) BRD8(2) BRD9 BRPF1 BRPF3 CECR2 FALZ PBRM1(2) PBRM1(5) PCAF SMARCA2 SMARCA4 TAF1(2) TAF1L(2) TRIM24(Bromo.) TRIM24(PHD,Bromo.) TRIM33(PHD,Bromo.) WDR9(2)
Probe Selectivity in Vitro:

In ExpresSProfile (CEREP) MT1 showed negligible activity for over 50 ligand receptors, ion channels and transport proteins. Partial inhibition of the NK2 receptor was observed. Shown is %specific control bound radioligand when incubated with 1 uM MT1: Assay, [control ligand]: %specific bound control; VPAC1 (VIP1),  [VIP]:     123.3; Y2,  [NPY]:     117.05; Y1, [NPY]:     115; CB1, [CP 55940]:     112.95; CCR1, [MIP-1a]:     108.65; D2S, [(+)butaclamol]:     108.15; GAL2, [galanin]:     107.8; B2, [NPC 567]:     106.55; D1, [SCH 23390]:     105.95; 5-HT transporter, [imipramine]:     104.2; α1 (non-selective), [prazosin]:    102.95; 5-HT6, [serotonin]:     102.05; GABA (non-selective), [GABA]:     101.65; sst (non-selective), [somatostatin-14]:     101.45; α2 (non-selective), [yohimbine]:    101.35; µ (MOP), [DAMGO]:     100.5; CXCR2 (IL-8B), [IL-8]:     100.35; KV channel, [a-dendrotoxin]:     100.1; 5-HT1A, [8-OH-DPAT]:     99; BZD, [diazepam]:     97.3; MC4, [NDP-a-MSH]:     96.7; M2, [methoctramine]:     96.4; β1, [atenolol]:     96.25; Ca2+ channel (L, verapamil site) (phenylalkylamine), [D 600]:     96; κ (KOP), [U 50488]:     95.4; 5-HT3, [MDL 72222]:     94.65; NOP (ORL1), [nociceptin]:     94.35; 5-HT5a, [serotonin]:     94.2; 5-HT7, [serotonin]:    93.8; A2A, [NECA]:     93.8; NTS1 (NT1), [neurotensin]:     93.4; EP4, [PGE2]:     92.9; norepinephrine transporter, [protriptyline]:     92.9; 5-HT2A, [ketanserin]:     92.55; M1, [pirenzepine]:     92.25; SKCa channel, [apamin]:     92.1; V1a, [[d(CH2)51,Tyr(Me)2]-AVP]:     92.05; Na+ channel (site 2), [veratridine]:  91.85; β2, [ICI 118551]:     91.65; Cl- channel (GABA-gated), [picrotoxinin]:     90.5; ETA, [endothelin-1]:     90.5; 5-HT1B, [serotonin]:     90.45; dopamine transporter, [BTCP]:     89.85; M3, [4-DAMP]:     89.65; AT1, [saralasin]:     88; NK3, [SB 222200]:     87.6; 5-HT2B, [(±)DOI]:     87.45; MT1 (ML1A), [melatonin]:     86.8; H1, [pyrilamine]:     86.6; CCK1 (CCKA), [CCK-8s]:     82.95; δ2 (DOP), [DPDPE]:     81.05; A1, [DPCPX]:     79.05; H2, [cimetidine]:     77.55; A3, [IB-MECA]:     73.7; NK2, [[Nleu10]-NKA (4-10)]:     24.25;

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This is a highly potent BET bromodomain inhibitor with more than 100-fold higher cellular potency than the corresponding monovalent antagonist JQ1. Potencies for the on-target proteins of the parent monovalent scaffold were profoundly increased by this bivalent ligand, whereas the activities for off-targets did not significantly increase. In vivo exposure following intraperitoneal dosing yielded strong efficacy in a leukemia mouse model.

(last updated: 28 Nov 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

MT1 is a bivalent BET bromodomain inhibitor, which is >100-fold more potent in the cell than the monovalent inhibitor JQ1. In a xenograpt model, MT1 treatment decreased tumor burden compared with JQ1. 

(last updated: 23 Dec 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 20 Jan 2017 )