Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2

Following the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of Imatinib in multiple models. Our results indicated that Imatinib and another TKI, the Masitinib, exhibit an antiviral activity in VeroE6 cells. However, Imatinib was inactive in a reconstructed bronchial human airway epithelium model. In vivo, Imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of Imatinib and similar TKIs as antivirals in the treatment of Covid-19.

COMPARATIVE RATIO OF BCR-ABL GENES WITH PCR METHOD USING THE CODIFICATION OF G6PD AND ABL GENES IN CHRONIC MYELOID LEUKEMIA PATIENTS (Perbandingan Angka Banding Gen BCR-ABL Metode PCR Menggunakan Baku Gen Glucosa-6-Phosphate Dehidrogenase dan Gen Abelson Kinase di Pasien Chronic Myeloid Leukemia)

Chronic Myeloid Leukemia (CML) adalah keganasan hematopoetik pertama yang dihubungkan dengan jejas genetik. Chronic MyeloidLeukemia digolongkan sebagai penyakit mieloproliferatif kronis disebabkan translokasi resiprokal kromosom 9 dan 22 yang disebutkromosom Philadelphia (Ph). Kromosom Ph membentuk gen yang disebut BCR-ABL. Pemeriksaan molekuler CML bertujuan untukmengetahui aktivitas transkripsi mRNA gen BCR-ABL, yang berguna untuk menetapkan diagnosis dan pemantauan pengobatan pasienCML. Saat ini, WHO mempublikasikan ada sembilan (9) gen baku yang digunakan secara luas. Tujuan penelitian ini adalah untukmengetahui angka banding gen BCR-ABL/G6PD dan BCR-ABL/ABL di pasien CML dengan kromosom Ph (+) secara membandingkan.Penelitian ini menggunakan 79 bahan biologis tersimpan (BBT) mRNA Ph (+) dari leukosit pasien CML yang datang ke RSUPDr. Hasan Sadikin Bandung selama masa waktu antara bulan April 2012−April 2014. Pemeriksaan angka banding gen BCR-ABL/G6PDdengan metode Real-time Quantification PCR menggunakan alat LightCycler® Roche. Angka banding gen BCR-ABL/ABL diperiksamenggunakan alat Bioneer®. Gen baku G6PD dapat mendeteksi tipe b2a2, b3a2 dan e1a2. Gen baku ABL hanya dapat mendeteksi tipeb2a2 dan b3a2, tetapi lebih stabil bila dibandingkan dengan gen baku G6PD. Bentuk penelitian adalah perbandingan analitik denganrancangan kajian potong lintang. Analisis statistik menggunakan uji nonparametrik Wilcoxon. Hasil angka banding mRNA gen BCRABL/G6PD dan gen BCR-ABL/ABL [1,93% (0,0–59,7 fg) vs 15,37% (0,04–35,7 kopi), p<0,001]. Gen BCR-ABL tidak terdeteksi di 3 BBTdengan menggunakan gen baku ABL. Berdasarkan telitian ini, dapat disimpulkan, bahwa terdapat perbedaan bermakna antara angkabanding gen BCR-ABL/G6PD dan yang terkait BCR-ABL/ABL. Gen baku yang sama diperlukan untuk mendiagnosis dan memantaurespons pengobatan.

FUSI GEN BREAKPOINT CLUSTER REGION ABELSON KINASE (BCRABL) DAN UJI HEMATOLOGIS RUTIN

Chronic myeloid leukemia (CML) is a type of Chronic myeloproliferative disorders in pluripotencial stem cell haematopoiesis cell disease caused by somatic mutation chromosomal translocation of the Abelson (ABL) and Breakpoint Cluster Region (BCR) genes on chromosomes 9 and 22. The Breakpoint Cluster Region Abelson Kinase (BCR-ABL) gene encodes different fusion transcripts of messenger Ribo Nucleic acid (m RNA)/type of fusion gene that vary in size depending on the breakpoint in the BCR gene. The majority of CMLcases have been shown to have either b3a2 or b2a2 fusion gene. This research is a preliminary study designed to know how to identify a quantification BCR-ABL gene and expression fusion of gene and its relation to routine haematological parameters. The researchers analyzed 12 adults who were positive using a quantification ratio BCR-ABL and Glucose-6-Phosphate Dehydrogenase (G6PDH) as a house keeping gene by real-time quantitative polymerase chain reaction (RQ PCR) of chronic phase of CML patients, qualitative of translocation of BCR-ABL gene by gel agarose and routine haematological tests by a haematologic analyzer. The average quantification ratio of BCRABL gene and G6PDH was 0.0881, 50% patients had b3a2 fusion gene, 41.6% had b2a2 dan 0.4% had e1a1. Fusion gene b3a2 showed a quantification ratio, haemoglobin level and leukocyte count higher compared to b2a2 fusion gene.

Abelson kinase acts as a robust, multifunctional scaffold in regulating embryonic morphogenesis

Abelson family kinases (Abls) are key regulators of cell behavior and the cytoskeleton during development and in leukemia. Abl’s SH3, SH2, and tyrosine kinase domains are joined via a linker to an F-actin–binding domain (FABD). Research on Abl’s roles in cell culture led to several hypotheses for its mechanism of action: 1) Abl phosphorylates other proteins, modulating their activity, 2) Abl directly regulates the cytoskeleton via its cytoskeletal interaction domains, and/or 3) Abl is a scaffold for a signaling complex. The importance of these roles during normal development remains untested. We tested these mechanistic hypotheses during Drosophila morphogenesis using a series of mutants to examine Abl’s many cell biological roles. Strikingly, Abl lacking the FABD fully rescued morphogenesis, cell shape change, actin regulation, and viability, whereas kinase-dead Abl, although reduced in function, retained substantial rescuing ability in some but not all Abl functions. We also tested the function of four conserved motifs in the linker region, revealing a key role for a conserved PXXP motif known to bind Crk and Abi. We propose that Abl acts as a robust multidomain scaffold with different protein motifs and activities contributing differentially to diverse cellular behaviors.

Dysregulated Dscam levels act through Abelson tyrosine kinase to enlarge presynaptic arbors

Increased expression of Down Syndrome Cell Adhesion Molecule (Dscam) is implicated in the pathogenesis of brain disorders such as Down syndrome (DS) and fragile X syndrome (FXS). Here, we show that the cellular defects caused by dysregulated Dscam levels can be ameliorated by genetic and pharmacological inhibition of Abelson kinase (Abl) both in Dscam-overexpressing neurons and in a Drosophila model of fragile X syndrome. This study offers Abl as a potential therapeutic target for treating brain disorders associated with dysregulated Dscam expression.