“Double-Hit” Chronic Lymphocytic Leukemia, Involving the TP53 and MYC Genes

Although the 17p deletion [del(17p)] is rare in cases of treatment-naive chronic lymphocytic leukemia (CLL), its frequency is higher in refractory/relapsed CLL – particularly in patients undergoing chemo(immuno)therapy. TP53 disruption (deletion and/or mutation) is the strongest prognostic factor for refractoriness to chemotherapy; the use of Bruton tyrosine kinase inhibitors and BCL2 inhibitors is then indicated. Rare cases of CLL can also harbor translocation or gain of the MYC oncogene. “Double-hit CLL” (with del(17p) and MYC gain) is associated with a very poor prognosis. The prognostic impact of TP53 disruption with MYC aberrations in patients receiving targeted therapies must now be evaluated.

HKSA secara In-Silico Senyawa 1-Benzil-3- Benzoilurea dan Analognya sebagai Penghambat Reseptor Bruton Tyrosine Kinase (BTK)

Abstract—In this study, a new anticancer drug design for non-Hodgkin’s lymphoma was carried out, with a molecular docking approach from the compound 1-benzyl-3-benzoylurea parent and its analog as an anticancer compound. The purpose of the study was to obtain the best quantitative structure-activity relationship (QSAR). The in-silico activity test was carried out on the new 1-benzyl-3-benzoilurea and its analog compound against the Bruton Tyrosine Kinase receptor (BTK) PDB code (5FBN) by using the Molegro Virtual Docker 5.5 program and producing a RS (Rerank Score) value for the test compound and Acalabrutinib was used as a comparison. This study also conducted bioavailability by predicting the value of F (intestinal human absorption) in the pkCSM program and toxicity studies by predicting LD50 values using the Protox II program. Correlation and regression were performed using the RS, F, and LD50 values that we obtained on the physicochemical properties of the test compound using the IBM SPSS version 24 program. The best equation is obtained as follows: (1) F = 0.851 Es Taft - 6.116 σ - 1.969 π² + 3.620 π + 90.809; (2) RS = 4.376 Es Taft - 88.802; (3) LD50 = 672.518 CMR - 669.385 ClogP - 813.806. From the results of the best equation is obtained that the activity is influenced by the parameters of steric physicochemical properties (Es Taft). Keywords: 1-benzyl-3-benzoylurea, code pdb:5fbn, in-silico, non-hodgkin lymphoma Abstrak—Pada penelitian ini dilakukan rancangan obat baru antikanker Limfoma non-Hodgkin, dengan pendekatan penambatan molekul dari senyawa induk 1-benzil-3-benzoilurea dan analognya sebagai senyawa antikanker.Tujuan penelitian ini untuk mendapatkan persamaan hubungan struktur aktivitas (HKSA) terbaik. Uji aktivitas in-silico dilakukan terhadap senyawa baru 1-benzil-3-benzoilurea dan analognya terhadap reseptor Bruton Tyrosine Kinase (BTK) kode PDB 5FBN dengan menggunakkan program Molegro Virtual Docker 5.5 dan menghasilkan nilai RS (Rerank Score) untuk senyawa uji dan Acalabrutinib digunakan sebagai pembanding. Penelitian ini juga dilakukan studi bioavaibilitas dengan memprediksi nilai F (intestinal human absorbtion) pada program pkCSM dan studi toksisitas dengan memprediksi nilai LD50 menggunakan program Protox II. Korelasi dan regresi dilakukan menggunakan nilai RS, F dan LD50 yang telah diperoleh terhadap parameter sifat fisikokimia senyawa uji menggunakan program IBM SPSS versi 24. Persamaan terbaik yang diperoleh sebagai berikut: (1) F = - 1.969 π² + 0.851 Es Taft - 6.116 σ + 3.620 π + 90.809 (2) RS = 4.376 Es Taft - 88.802 (3) LD50 = 672.518 CMR - 669.385 ClogP - 813.806. Dari hasil persamaan terbaik tersebut diperoleh bahwa aktivitas dipengaruhi oleh parameter sifat fisikokimia sterik (Es Taft). Kata kunci: 1-benzil-3-benzoilurea, in-silico, kode pdb: 5fbn, limfoma non-hodgkin

Inhibition of Bruton Tyrosine Kinase Reduces Neuroimmune Cascade and Promotes Recovery after Spinal Cord Injury

Microglia/astrocyte and B cell neuroimmune responses are major contributors to the neurological deficits after traumatic spinal cord injury (SCI). Bruton tyrosine kinase (BTK) activation mechanistically links these neuroimmune mechanisms. Our objective is to use Ibrutinib, an FDA-approved BTK inhibitor, to inhibit the neuroimmune cascade thereby improving locomotor recovery after SCI. Rat models of contusive SCI, Western blot, immunofluorescence staining imaging, flow cytometry analysis, histological staining, and behavioral assessment were used to evaluate BTK activity, neuroimmune cascades, and functional outcomes. Both BTK expression and phosphorylation were increased at the lesion site at 2, 7, 14, and 28 days after SCI. Ibrutinib treatment (6 mg/kg/day, IP, starting 3 h post-injury for 7 or 14 days) reduced BTK activation and total BTK levels, attenuated the injury-induced elevations in Iba1, GFAP, CD138, and IgG at 7 or 14 days post-injury without reduction in CD45RA B cells, improved locomotor function (BBB scores), and resulted in a significant reduction in lesion volume and significant improvement in tissue-sparing 11 weeks post-injury. These results indicate that Ibrutinib exhibits neuroprotective effects by blocking excessive neuroimmune responses through BTK-mediated microglia/astroglial activation and B cell/antibody response in rat models of SCI. These data identify BTK as a potential therapeutic target for SCI.

Zanubrutinib (Brukinsa)

CADTH recommends that Brukinsa be reimbursed by public drug plans for the treatment of adult patients with relapsed or refractory Waldenström macroglobulinemia (WM), if certain conditions are met. Brukinsa should only be covered to treat patients with relapsed or refractory WM who have received at least 1 prior line of therapy, meet at least 1 criterion for treatment according to International Workshop on WM (IWWM) consensus panel criteria, and have good performance status. Patients eligible for reimbursement of Brukinsa should not have disease transformation, which is WM that has transformed into another type of cancer, or received prior treatment with a drug of the same class (i.e., a Bruton tyrosine kinase [BTK] inhibitor) unless such therapy was stopped because the drug was not tolerated and the disease had not progressed. Brukinsa should only be reimbursed if prescribed by a clinician with expertise and experience in the treatment of WM and monitoring of therapy and if it does not cost more than other treatments for WM.

Study of Molecular Docking, Molecular Dynamic and Toxicity Prediction of Several Quinoline Alkaloid Derivatives as a Bruton Tyrosine Kinase Inhibitor as Anti-Leukemia

Quinoline alkaloid and its derivatives play a vital role in the development of new therapeutic agents. Cinnoline structure has similarities with quinoline alkaloid compound and has the potential to inhibit Bruton’s Tyrosine Kinase (BTK) in leukemia treatment. This research aims to study the interaction of several quinoline alkaloids with BTK and to predict the toxicity to ensure their safety. This study was carried out using computational studies, including molecular docking, molecular dynamics simulation, and toxicity prediction, to assess the compound’s activity towards BTK and their toxicity. Molecular docking simulations showed that ten compounds (S1, S2, S4, S5, S8, S13, S14, S16, S17, and S20) had the best affinity to BTK. Molecular dynamics simulations to these ten compounds showed that only seven compounds (S1, S5, S8, S13, S16, S17, and S20) could stabilize the interaction towards BTK with RMSD and RMSF value of 0.5 ± 2 Å and 0.5 ± 6, 5 Å, respectively. Toxicity prediction results showed that these quinoline alkaloids had various toxicity characteristics, but most were not carcinogens and mutagens (S4, S5, S6, S7, S8, S10 S11, S12, S14, and S15). It can be concluded that Yukositrin (S8) has the most potential affinity towards BTK, which can be used as anti-leukemia with low toxicity. Keywords: anti-leukemia, Bruton Tyrosine Kinase, docking, MD, quinoline alkaloids