477846-55-2Relevant articles and documents
The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations
Chai, Yingying,Chen, Hai,He, Yang,Huang, Ridong,Li, Weimin,Li, Ying,Ma, Lingling,Xia, Zhenqiang,Yu, Quanwei,Zhou, Xinglong
, (2021/07/28)
EGFR mutations are an ongoing challenge in the treatment of NSCLC, and demand continuous updating of EGFR TKI drug candidates. Pyrrolopyrimidines are one group of versatile scaffolds suitable for tailored drug development. However not many precedents of this type of pharmacophore have been investigated in the realm of third generation of covalent EGFR-TKIs. Herein, a series of pyrrolo[2,3-d]pyrimidine derivatives able to block mutant EGFR activity in a covalent manner were synthesized, through optimized Buchwald-Hartwig C–N cross coupling reactions. Their preliminary bioactivity and corresponding inhibitory mechanistic pathways were investigated at molecular and cellular levels. Several compounds exhibited increased biological activity and enhanced selectivity compared to the control compound. Notably, compound 12i selectively inhibits HCC827 cells harboring the EGFR activating mutation with up to 493-fold increased efficacy compared to in normal HBE cells. Augmented selectivity was also confirmed by kinase enzymatic assay, with the test compound selectively inhibiting the T790 M activating mutant EGFRs (IC50 values of 0.21 nM) with up to 104-fold potency compared to the wild-type EGFR (IC50 values of 22 nM). Theoretical simulations provide structural evidence of selective kinase inhibitory activity. Thus, this series of pyrrolo[2,3-d]pyrimidine derivatives could serve as a starting point for the development of new EGFR-TKIs.
Pyrrolo [2, 3-d] pyrimidine derivative targeting EGFR mutation as well as preparation method and application of pyrrolo [2, 3-d] pyrimidine derivative
-
, (2020/11/10)
The invention provides a pyrrolo [2, 3-d] pyrimidine derivative targeting EGFR mutation as well as a preparation method and application thereof, and belongs to the field of chemical medicines. The derivative is a compound shown as a formula I, or a salt t
Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[14.3.1.13,7.1 9,13]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles
Breslin, Henry J.,Lane, Brandon M.,Ott, Gregory R.,Ghose, Arup K.,Angeles, Thelma S.,Albom, Mark S.,Cheng, Mangeng,Wan, Weihua,Haltiwanger, R. Curtis,Wells-Knecht, Kevin J.,Dorsey, Bruce D.
, p. 449 - 464 (2012/03/10)
A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.13,7.1 9,13]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC50 = 0.5 nM) and cellular (IC50 = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.
MACROCYCLIC COMPOUNDS AS ALK, FAK AND JAK2 INHIBITORS
-
Page/Page column 56-57, (2012/10/07)
The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.
