Guanidino quinazolines and pyrimidines promote readthrough of premature termination codons in cells with native nonsense mutations.

Autor: Morrill C; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA. Electronic address: cmorrill@ptcbio.com., Friesen WJ; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Babu S; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Baiazitov RY; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Du W; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Karloff DB; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Lee CS; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Moon YC; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Ren H; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Sierra J; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Tomizawa Y; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Vazirani P; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Welch EM; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Xue X; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA., Zhuo J; PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Nov 15; Vol. 76, pp. 128989. Date of Electronic Publication: 2022 Sep 20.
DOI: 10.1016/j.bmcl.2022.128989
Abstrakt: Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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