In:
ChemMedChem, Wiley, Vol. 15, No. 7 ( 2020-04-03), p. 643-658
Abstract:
Abstract : LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying aroyl‐ and arylacetylamino ( 1 a – h ), Z ‐amino acylamino ( 2 a – o ), or double‐substituted benzamide ( 3 a – n ) residues at the C4 or C3 position of the phenyl ring. Further fragments obtained by chemical manipulation applied on the TCP scaffold (compounds 4 a – i ) were also prepared. When tested against LSD1, most of 1 and 3 exhibited IC 50 values in the low nanomolar range, with 1 e and 3 a , d , f , g being also the most selective respect to monoamine oxidases. In MV4‐11 AML and NB4 APL cells compounds 3 were the most potent, displaying up to sub‐micromolar cell growth inhibition against both cell lines ( 3 a ) or against NB4 cells ( 3 c ). The most potent compounds in cellular assays were also able to induce the expression of LSD1 target genes, such as GFI‐1b , ITGAM , and KCTD12 , as functional read‐out for LSD1 inhibition. Mouse and human intrinsic clearance data highlighted the high metabolic stability of compounds 3 a , 3 d and 3 g . Further studies will be performed on the new compounds 3 a and 3 c to assess their anticancer potential in different cancer contexts.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201900730
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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