T-3775440 hydrochloride

T-3775440 (hydrochloride) is an irreversible lysine-specific histone demethylase (LSD1) inhibitor with an IC50 value of 2.1 nM.

Product information

CAS Number: 1422535-52-1

Molecular Weight: 346.85

Formula: C18H23ClN4O

Chemical Name: N-{4-[(1S,2R)-2-[(cyclopropylmethyl)amino]cyclopropyl]phenyl}-1-methyl-1H-pyrazole-4-carboxamide hydrochloride

Smiles: Cl.CN1C=C(C=N1)C(=O)NC1C=CC(=CC=1)[C@@H]1C[C@H]1NCC1CC1

InChiKey: XYFPAGOQZFSLFH-MCJVGQIASA-N

InChi: InChI=1S/C18H22N4O.ClH/c1-22-11-14(10-20-22)18(23)21-15-6-4-13(5-7-15)16-8-17(16)19-9-12-2-3-12;/h4-7,10-12,16-17,19H,2-3,8-9H2,1H3,(H,21,23);1H/t16-,17+;/m0./s1

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO : ≥ 30.18 mg/mL (87.01 mM).

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

T-3775440 demonstrates irreversible inhibition of recombinant human LSD1, with a kinact/KI value of 1.7×105 (sec−1 M−1). T-3775440 is highly selective for LSD1 relative to other monoamine oxidases (e.g., MAO-A and MAO-B), with an IC50 value of 2.1 nM). T-3775440 blocks the proliferation of several cell lines as quickly as day 3 of treatment. Notably, the granulocyte/macrophage markers CD86 and CD11b are commonly upregulated on both TF-1a and HEL92.1.7 cells in response to T-3775440 treatment, whereas the erythroid markers CD235a and CD71 are downregulated by this treatment. In CMK11-5 cells, CD86 mRNA expression is also clearly upregulated by T-3775440 in a concentration-dependent manner, although only a modest increase in cell surface CD86 expression is observed. T-3775440 treatment disrupts the LSD1-GFI1B association in a concentration-dependent manner. T-3775440 decreases LSD1 binding but not GFI1B binding and increases the level of dimethylated H3K4 at the PI16 locus.

In Vivo:

T-3775440 upregulates CD86 mRNA expression in tumor xenografts of HEL92.1.7 cells in a dose-dependent manner following the oral administration of single doses ranging from 3 to 30 mg/kg. To investigate target engagement of this compound in tumors, PI16 expression levels is tested as a direct biomarker. As expected, PI16 suppression is dramatically reversed by T-3775440 treatment. In a TF-1a (AEL) tumor xenograft model, T-3775440 exhibits significant antitumor effects, with 15-day T/C values of 15.6% and <0% at doses of 20 and 40 mg/kg, respectively. T-3775440 also exhibits potent antitumor effects in an additional AEL model of HEL 92.1.7 and an AMKL model of CMK11-5, leading to nearly complete tumor growth suppression during the dosing period. It is found that in mice, T-3775440 treatment results in a transient reduction in platelets, followed by a significant rebound; this is considered a mechanism-based adverse effect of LSD1 inhibition. On a dosing schedule comprising 5 days on/2 days off, a statistically significant difference in body weight is observed between vehicle- and T-3775440–treated tumor xenograft model mice at higher doses. However, efficacious T-3775440 doses are tolerated in all subcutaneous tumor xenograft models.

Products are for research use only. Not for human use.