T-3775440 hydrochloride

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种新型有效、选择性、不可逆的 LSD1 抑制剂，IC50 为 2.1 nM。

A novel potent, selecitve, irreversible LSD1 inhibitor with IC50 of 2.1 nM; displays high selectivity for LSD1 relative to other monoamine oxidases (e.g., MAO-A and MAO-B); disrupts the interaction between LSD1 and growth factor-independent 1B (GFI1B) in leukemia cell lines, exhibites significant antitumor efficacy in AEL and AMKL xenograft models.

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.

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.

T 3775440 | T3775440

Chromatin/Epigenetic

Histone Demethylase

Histone Demethylase

Cancer

——

1422535-52-1

346.859

C18H23ClN4O

>98% (HPLC)

DMSO : ≥ 30.18 mg/mL 87.01 mM

CN1C=C(C=N1)C(=O)NC2=CC=C(C=C2)C3CC3NCC4CC4.Cl

N-(4-((1S,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide hydrochloride

(-20℃)

With Ice Pack

≥ 2 years