Three Dimensional Quantitative Structure-Activity Relationship of 5H-Pyrido[4,3-b]indol-4-carboxamide JAK2 Inhibitors

Xiaoyun Wu,Shanhe Wan,Jiajie Zhang

doi:10.3390/ijms140612037

Abstract

Janus kinase 2 (JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family of kinases, which play an important role in survival, proliferation, and differentiation of a variety of cells. JAK2 inhibitors are potential drugs for the treatment of myeloproliferative neoplasms. The three dimensional quantitative structure-activity relationships have been studied on a series of JAK2 inhibitors by comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The CoMFA model had a cross-validated coefficient q2 of 0.633, and the relation non-cross-validated coefficient r2 of 0.976. The F value is 225.030. The contributions of steric and electrostatic fields to the activity are 55.2% and 44.8%, respectively. For the CoMSIA study, the q2, r2, and F values of the model are 0.614, 0.929, and 88.771, respectively. The contributions of steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond donor fields to the activity are 27.3%, 23.9%, 16.4%, 21.7%, and 10.7%, respectively. The CoMFA and CoMSIA models showed strong predictive ability, and the 3D contour plots give the basis on the structure modification of JAK2 inhibitors.

Highlights

Janus kinase 2 (JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family kinases (JAK1, JAK2, JAK3, and TYK2), which is important in many of cellular signaling pathways [1,2,3]
JAK2 is essential for hematopoiesis, platelet formation, and other functions that are important in cellular survival, proliferation, and differentiation
In 2005, several groups independently reported the discovery of a somatic mutation of the gene encoding JAK2 in a high proportion of patients with myeloproliferative neoplasms (MPNs) : >95% for polycythemia vera (PV), and 50% for essential thrombocythemia (ET) and primary myelofibrosis (PMF) [4,5,6,7,8]

Summary

Introduction

Janus kinase 2 (JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family kinases (JAK1, JAK2, JAK3, and TYK2), which is important in many of cellular signaling pathways [1,2,3]. JAK2 is essential for hematopoiesis, platelet formation, and other functions that are important in cellular survival, proliferation, and differentiation. In 2005, several groups independently reported the discovery of a somatic mutation of the gene encoding JAK2 in a high proportion of patients with myeloproliferative neoplasms (MPNs) : >95% for polycythemia vera (PV), and 50% for essential thrombocythemia (ET) and primary myelofibrosis (PMF) [4,5,6,7,8].

Methods

Results

Conclusion