93683-65-9Relevant articles and documents
Optimization of 4,6-Disubstituted Pyrido[3,2-d]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth
Han, Yu,Zhang, Huimin,Wang, Shuxiang,Li, Bo,Xing, Kun,Shi, Yuntao,Cao, Hongxue,Zhang, Jian,Tong, Tong,Zang, Jie,Guan, Lihong,Gao, Xiaoxiao,Wang, Yuetong,Liu, Dan,Huang, Min,Jing, Yongkui,Zhao, Linxiang
, p. 13719 - 13735 (2021/10/01)
Mitogen-activated protein kinase-interacting kinases (MNKs) and provirus integration in maloney murine leukemia virus kinases (PIMs) are downstream enzymes of cell proliferation signaling pathways associated with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have complementary effects to regulate cap-dependent translation of oncoproteins. Dual inhibitors of MNKs and PIMs have not been developed. We developed a novel 4,6-disubstituted pyrido[3,2-d]pyrimidine compound 21o with selective inhibition of MNKs and PIMs. The IC50’s of 21o to inhibit MNK1 and MNK2 are 1 and 7 nM and those to inhibit PIM1, PIM2, and PIM3 are 43, 232, and 774 nM, respectively. 21o inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI50’s of 2.1 and 1.2 μM, respectively. 21o decreases the levels ofp-eIF4E andp-4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.
Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection
Shah, Khushbu,Queener, Sherry,Cody, Vivian,Pace, Jim,Gangjee, Aleem
, p. 1874 - 1880 (2019/06/08)
Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2-d]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors.
MONOCYCLIC, THIENO, PYRIDO, AND PYRROLO PYRIMIDINE COMPOUNDS AND METHODS OF USE AND MANUFACTURE OF THE SAME
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, (2017/03/21)
The present invention provides monocyclic, thieno, pyrido and pyrrolo pyrimidine compounds. Pharmaceutical compositions comprising one or more of these compounds and optionally comprising a pharmaceutically acceptable salt or hydrate of one or more of the compounds are provided. Preferably, these pharmaceutical compositions further comprise at least one pharmaceutically acceptable carrier. Methods of treating a patient having cancer are provided wherein a therapeutically effective amount of one or more of these compounds or pharmaceutical compositions are administered to the patient.
