Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, 110016, China.
J Med Chem. 2021 Sep 23;64(18):13719-13735. doi: 10.1021/acs.jmedchem.1c01084. Epub 2021 Sep 13.
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-]pyrimidine compound with selective inhibition of MNKs and PIMs. The IC's of 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. inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI's of 2.1 and 1.2 μM, respectively. decreases the levels of -eIF4E and -4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.
有丝分裂原活化蛋白激酶相互作用激酶（MNKs）和原病毒整合的莫洛尼鼠白血病病毒激酶（PIMs）是与酪氨酸激酶抑制剂耐药相关的细胞增殖信号通路的下游酶。MNKs 和 PIMs 具有互补作用，可调节癌蛋白的帽依赖性翻译。尚未开发出 MNKs 和 PIMs 的双重抑制剂。我们开发了一种新型的 4,6-二取代吡啶并[3,2-]嘧啶化合物 ，对 MNKs 和 PIMs 具有选择性抑制作用。对 MNK1 和 MNK2 的抑制常数（IC）分别为 1 和 7 nM，对 PIM1、PIM2 和 PIM3 的抑制常数分别为 43、232 和 774 nM。化合物 对髓性白血病 K562 和 MOLM-13 细胞的生长具有 GI 值，分别为 2.1 和 1.2 μM。化合物 降低了 MNKs 和 PIMs 的下游产物 -eIF4E 和 -4EBP1 以及帽依赖性蛋白 c-myc、cyclin D1 和 Mcl-1 的水平。化合物 抑制 MOLM-13 细胞异种移植物的生长而没有引起明显的毒性。化合物 代表了一种具有良好药代动力学特征的创新型双重 MNK/PIM 抑制剂。
