Identification of a new family of pyrazolo[3,4-d]pyrimidine derivatives as multitarget Fyn-Blk-Lyn inhibitors active on B- and T-lymphoma cell lines

Anna Lucia Fallacara; Raffaele Passannanti; Mattia Mori; Giulia Iovenitti; Francesca Musumeci; Chiara Greco; Emmanuele Crespan; Miroslava Kissova; Giovanni Maga; Chiara Tarantelli; Filippo Spriano; Eugenio Gaudio; Francesco Bertoni; Maurizio Botta; Silvia Schenone

doi:10.1016/j.ejmech.2019.07.048

Identification of a new family of pyrazolo[3,4-d]pyrimidine derivatives as multitarget Fyn-Blk-Lyn inhibitors active on B- and T-lymphoma cell lines

Eur J Med Chem. 2019 Nov 1:181:111545. doi: 10.1016/j.ejmech.2019.07.048. Epub 2019 Jul 18.

Authors

Affiliations

¹ Department of Biotechnology, Chemistry and Pharmacy, "Department of Excellence 2018-2022", University of Siena, Via Aldo Moro 2, 53100, Siena, Italy.
² Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132, Genoa, Italy.
³ Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, I-27100, Pavia, Italy.
⁴ Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), via Vela 6, 6500, Bellinzona, Switzerland.
⁵ Department of Biotechnology, Chemistry and Pharmacy, "Department of Excellence 2018-2022", University of Siena, Via Aldo Moro 2, 53100, Siena, Italy; Biotechnology College of Science and Technology, Temple University, Biolife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA, 19122, United States; Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo, Berardenga, Italy. Electronic address: botta.maurizio@gmail.com.

PMID: 31400706
DOI: 10.1016/j.ejmech.2019.07.048

Abstract

Abnormal activation of B-cell receptor (BCR) signaling plays a key role in the development of lymphoid malignancies, and could be reverted by the simultaneous inhibition of Lyn, Fyn and Blk, three members of the Src family kinase (SFK). Fyn and Blk are also promising targets for the treatment of some forms of T-cell non-Hodgkin lymphoma which point to the druggability of SFKs for the treatment of these cancers. We recently identified Si308 as a potent Fyn inhibitor, while preliminary data showed that it might also inhibit Lyn and Blk. Here, molecular modelling studies were coupled with enzymatic assays to further investigate the effect of Si308 on Lyn and Blk. A small library of pyrazolo[3,4-d]pyrimidines structurally related to Si308 was synthesized and tested on human lymphoma cell lines. Compound 2h emerged as a new multitarget inhibitor of Lyn, Fyn and Blk endowed with remarkable antiproliferative effects on human B and T lymphoma cell lines. Its favorable ADME properties make the compound suitable for further developments.

Keywords: Blk; Fyn; Kinase inhibitor; Lymphoma; Lyn; pyrazolo[3,4-d]pyrimidine.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Lymphoma, T-Cell / drug therapy*
Lymphoma, T-Cell / metabolism
Lymphoma, T-Cell / pathology
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins c-fyn / antagonists & inhibitors*
Proto-Oncogene Proteins c-fyn / metabolism
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
src-Family Kinases / antagonists & inhibitors*
src-Family Kinases / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
pyrazolo(3,4-d)pyrimidine
Protein-Tyrosine Kinases
BLK protein, human
FYN protein, human
Proto-Oncogene Proteins c-fyn
lyn protein-tyrosine kinase
src-Family Kinases