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TACH101

TACH101 : Inhibitor of KDM4 family members KDM4A, KDM4B, KDM4C, KDM4D

Structure

Information

  • KDM4A
  • KDM4B
  • KDM4C
  • KDM4D
  • Inhibitor
  • up to 1 uM

In Vitro Validations

Uniprot ID: O75164
Target Class: Epigenetic
Target SubClass: Histone demethylase
Potency: IC50
Potency Value: 80 nM
Potency Assay: Enzymatic assay (LANCE TR-FRET) with pre-incubation with TACH101 in presence of alpha-KG
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Lysine-specific demethylase 4A, KIAA0677, JMJD2A, ...

DOI Reference: 10.1097/CAD.0000000000001514

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay (off target): The selectivity of TACH101 was assessed against KDM family members 2–7. TACH101 was observed to exhibit selective and potent inhibition of KDM4 isoforms A–D (IC50 ≤ 0.080 µmol/l) when preincubated for 60 min before the initiation of inhibition assays. Without preincubation, TACH101 was less potent in inhibiting KDM4 isoforms A and C than the corresponding outcomes with incubation
Probe Selectivity in Vitro:
Without preincubation, TACH101 inhibited KDM5 family members at potencies ranging from 0.14 to 0.40 µmol/l. However, binding was not time-dependent, and TACH101 IC50 following preincubation was slightly less potent for KDM5B and significantly less potent for KDM5A, relative to no preincubation. TACH101 showed significantly lower potency against KDM2, KDM3, KDM6, and KDM7 family members with or without preincubation.
Potency assay, off target (cells): TACH101 antiproliferative activity was determined across a broad cancer cell line panel composed of 301 cancer cell lines originating from 24 different hematologic and solid cancer types. Results demonstrate that TACH101 displayed a highly selective potency profile, with IC50 values ranging from less than 500 pM to more than 10 µmol/l. Among the 301 cell lines, 209 were inhibited by TACH101 with IC50 values < 1 µmol/l, whereas 89 lines were insensitive with IC50 values ≥ 10 µmol/l.
Potency assay, off target (cells): The antiproliferative activity of TACH101 was also tested in patient-derived cancer organoid models. The IC50 values for TACH101 inhibition of colony formation and viability were determined for colon cancer organoid models (SU60, T002C, SU62, SU34, SU103, T035C, and SU106), pancreatic cancer organoid models (PA0165F, PA0143F, T016P, and T028P), and a breast cancer organoid model (FS53). TACH101 treatment demonstrated submicromolar antiproliferative activity for SU60, T002C, and SU62 CRC models yielding IC50 values < 0.15 µmol/l.
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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

TACH101 is high-quality probe with selectivity for the KDM4 family of Jumonji (JMJ) demethylases. Both in vitro and cellular on-target effects are observed in the low nanomolar range. Cancer cell line toxicity can occur across a wide range of doses depending on the model type. A structurally related probe, QC6352, is a similar tool compound with similar activity both in vitro, cells, and in vivo (Chen et al.; PMID:28835804).

(last updated: 7 May 2025 )

SERP Ratings

In Cell Rating

SERP Comments:

This is a pan-KDM4 inhibitor currently tested in clinical trials. In vitro, there seems only a small selectivity window to KDM5 inhibition. No unbiased data on cellular binding specificity e.g. by chemical proteomics to thermal proteome profiling are published. Some of the cellular effects on proliferation and histone methylation are observed at significantly lower concentrations compared to in vitro demethylase inhibition, suggesting more data are necessary to assess the selectivity of this compound.

(last updated: 13 May 2025 )