Articles Related to Drug Design
Mechanisms of Resistance to Kinase Inhibitors and Strategies to Prevent the Development of Drug Resistance
Targeting mutant proteins and associated signaling pathways of driver oncogenes by small molecule kinase inhibitors (KIs) are a
promising strategy of cancer therapy. However, despite the initial success of treatment, KIs often become ineffective as intrinsic and
acquired resistance. This article reviews the English-language literature to explore the underlying mechanisms of drug resistance and
to present a challenge for developing drugs to overcome resistance. Mechanisms of acquired resistance include 1) the selection of
pre-existing subclones with other mutations, 2) the emergence of secondary mutations in the target kinase domain, 3) upregulation
of kinases both within the same kinase family and their related kinase families, as well as activation of alternative bypass pathways, 4)
epithelial-mesenchymal transition, 5) overexpression of pro-survival Bcl-2 family proteins and 6) drug efflux mechanisms. Currently
available methods are to obtain tumor biopsy samples at recurrence or progression if the tumor lesion is accessible to a biopsy and to
use the second- and third-generation KIs based on the individual need of each patient. Furthermore, recent computational challenges
provide design principles to prevent the development of drug resistance. In conclusion, we provide an overview of the postulated
resistance mechanisms and highlight the future direction of computational structure-based design of new potent KIs.
Editorial Board Members Related to Drug Design
Mohammad Ayoub Mir
Assistant Professor
School of Medicine
University of Kansas
United States
School of Medicine
University of Kansas
United States
MD Ibrahim El Said Ali El-Gamal
Assistant Professor
College of Pharmacy
Department of Medicinal Chemistry
University of Sharjah
UAE
College of Pharmacy
Department of Medicinal Chemistry
University of Sharjah
UAE
PANKAJ P. KAPUPARA
Associate Professor
School of Pharmacy
RK University
Rajkot
India
School of Pharmacy
RK University
Rajkot
India
Xinyong Liu
Professor
School of Pharmaceutical Sciences
Shandong University
China
School of Pharmaceutical Sciences
Shandong University
China
K. RAMANATHAN
Associate Professor
Industrial Biotechnology Division
School of Bio Sciences and Technology
VIT University
INDIA
Industrial Biotechnology Division
School of Bio Sciences and Technology
VIT University
INDIA
Suman Sirimulla
Assistant Professor
Department of Basic Sciences
St. Louis College of Pharmacy
St. Louis, MO
United States.
Department of Basic Sciences
St. Louis College of Pharmacy
St. Louis, MO
United States.
Emil Bulatov
Associate Professor
Department of Chemical Biology Group
Institute of Fundamental Medicine and Biology
Kazan Federal University
Russia
Department of Chemical Biology Group
Institute of Fundamental Medicine and Biology
Kazan Federal University
Russia
Marwa Hamdy El-Wakil
Faculty of Pharmacy
Pharmaceutical Chemistry Department
Alexandria University
Egypt
Pharmaceutical Chemistry Department
Alexandria University
Egypt
Peng Zhan
Associate professor
School of pharmaceutical sciences
Shandong University
China
School of pharmaceutical sciences
Shandong University
China
Prakash Prajapat
Assistant Professor
Department of Chemistry
Mehsana Urban Institute of Sciences
Ganpat University
Gujarat.
Department of Chemistry
Mehsana Urban Institute of Sciences
Ganpat University
Gujarat.