2. Academic Validation
  3. Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265P Mutant Diffuse Large B Cell Lymphoma

Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265P Mutant Diffuse Large B Cell Lymphoma

  • J Med Chem. 2019 Nov 14;62(21):9918-9930. doi: 10.1021/acs.jmedchem.9b01346.
Sébastien L Degorce 1,  Rana Anjum 2,  Andrew Bloecher 2,  Rodrigo J Carbajo 1,  Keith S Dillman 2,  Lisa Drew 2,  Christopher T Halsall 1,  Eva M Lenz 1,  Nicola A Lindsay 1,  Michele F Mayo 2,  Jennifer H Pink 1,  Graeme R Robb 1,  Alan Rosen 2,  James S Scott 1,  Yafeng Xue 3
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Oncology R&D , AstraZeneca , Cambridge Science Park , Unit 310 Darwin Building, Cambridge CB4 0WG , U.K.
  • 2 Bioscience, Oncology R&D , AstraZeneca, Boston , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States.
  • 3 Discovery Sciences, R&D , AstraZeneca , Gothenburg SE-431 83 , Mölndal , Sweden.
PMID: 31622099 DOI: 10.1021/acs.jmedchem.9b01346
Abstract

In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 Inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130253
    99.92%, IRAK抑制剂
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