Alkynylnicotinamide-Based Compounds as ABL1 Inhibitors with Potent Activities against Drug-Resistant CML Harboring ABL1(T315I) Mutant Kinase

Elizabeth A Larocque; N Naganna; Clement Opoku-Temeng; Alyssa M Lambrecht; Herman O Sintim

doi:10.1002/cmdc.201700829

Alkynylnicotinamide-Based Compounds as ABL1 Inhibitors with Potent Activities against Drug-Resistant CML Harboring ABL1(T315I) Mutant Kinase

ChemMedChem. 2018 Jun 20;13(12):1172-1180. doi: 10.1002/cmdc.201700829. Epub 2018 May 22.

Authors

Elizabeth A Larocque¹, N Naganna¹, Clement Opoku-Temeng^{1

2}, Alyssa M Lambrecht¹, Herman O Sintim¹

Affiliations

¹ Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
² Graduate Program in Biochemistry, University of Maryland, College Park, MD, 20742, USA.

Abstract

The introduction of imatinib into the clinical scene revolutionized the treatment of chronic myelogenous leukemia (CML). The overall eight-year survival rate for CML has increased from about 6 % in the 1970s to over 90 % in the imatinib era. However, about 20 % of CML patients harbor primary or acquired resistance to tyrosine kinase inhibitors. ABL1 point mutations in the BCR-ABL1 fusion protein, such as ABL1(T315I), typically emerge after prolonged kinase inhibitor treatment. Ponatinib (AP24534) is currently the only approved CML drug that is active against the ABL1(T315I) mutation. However, ponatinib has severe cardiovascular toxicities; hence, there have been efforts to find safer CML drugs that work against ABL1 secondary mutations. We reveal that isoquinoline- or naphthyridine-based compounds, such as HSN431, HSN576, HSN459, and HSN608 potently inhibit the enzymatic activities of ABL1, ABL1(T315I), and ABL1(E255K). These compounds inhibit the proliferation of ABL1-driven CML cell lines, K652 and KCL22 as well as the drug-resistant cell line, KCL22-IR, which harbors the secondary mutated ABL1(T315I) kinase.

Keywords: BCR-ABL; anticancer agents; chronic myelogenous leukemia; drug resistance; kinase.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alkynes / chemical synthesis
Alkynes / chemistry
Alkynes / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Humans
Imatinib Mesylate / pharmacology
Imidazoles / pharmacology
Isoquinolines / chemical synthesis
Isoquinolines / chemistry
Isoquinolines / pharmacology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Mice
Molecular Docking Simulation
Naphthyridines / chemical synthesis
Naphthyridines / chemistry
Naphthyridines / pharmacology
Niacinamide / analogs & derivatives*
Niacinamide / chemical synthesis
Niacinamide / chemistry
Niacinamide / pharmacology*
Point Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
Proto-Oncogene Proteins c-abl / chemistry
Proto-Oncogene Proteins c-abl / genetics
Pyridazines / pharmacology
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology

Substances

Alkynes
Antineoplastic Agents
Imidazoles
Isoquinolines
Naphthyridines
Protein Kinase Inhibitors
Pyridazines
Quinazolines
Niacinamide
ponatinib
Imatinib Mesylate
ABL1 protein, human
Proto-Oncogene Proteins c-abl

Grants and funding

P30 CA023168/CA/NCI NIH HHS/United States