Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC: 7 nM) irreversible BTK inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35) = 0.00) among 468 kinases/mutants at the concentration of 1 μM. Compound 9 completely abolished BMX, JAK3 and EGFR's activity. Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode. 9 also potently inhibited BTK Y223 auto-phosphorylation (EC: <30 nM), arrested cell cycle in G0/G1 phase and induced apoptosis in U2932 and Pfeiffer cells. We believe these features would make 9 a good pharmacological tool to study the BTK related pathology.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ejmech.2017.03.001 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Severe atypical skin disease in two patients with CLL/SLL after BTKi treatment - a case report and literature review.
Front Oncol
December 2024
Department of Hematology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, Jiangsu, China.
Dermatological adverse events (AEs) are generally mild during therapy with Bruton's tyrosine kinase inhibitor (BTKi), and it is often unnecessary to adjust the BTKi dosage or discontinue treatment. However, in this study, we present the cases of two patients diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who experienced severe dermatological AEs during BTKi treatment and subsequently had to discontinue it. The first patient, who previously suffered from rashes, experienced rashes again along with fever when exposed to BTKi.
View Article and Find Full Text PDFMolecular Profiling Identifies CD49d and CD79b as Predictive Markers for Acquired Acalabrutinib Resistance in Patients With Chronic Lymphocytic Leukemia.
Hematol Oncol
January 2025
Hematology, Oncology R&D, AstraZeneca, Cambridge, UK.
Contemporary studies of Bruton tyrosine kinase inhibitor (BTKi) resistance focus on mutations in the B-cell receptor (BCR) pathway, but alternative mechanisms of resistance remain undefined. Here, we sought to identify novel predictive markers of acquired resistance to acalabrutinib, a second-generation BTKi, in patients with chronic lymphocytic leukemia (CLL). Clinical samples from 41 patients with relapsed/refractory or treatment-naive CLL receiving acalabrutinib as part of a clinical trial (NCT02029443) were divided into two groups: those who continued to respond to treatment (NP, n = 23) and those who developed progressive disease on acalabrutinib therapy (PD, n = 18).
View Article and Find Full Text PDFIdentifying potential drug-drug interactions (DDIs) before clinical use is essential for patient safety yet remains a significant challenge in drug development. We presented DDI-GPT, a deep learning framework that predicts DDIs by combining knowledge graphs (KGs) and pre-trained large language models (LLMs), enabling early detection of potential drug interactions. We demonstrated that DDI-GPT outperforms current state-of-the-art methods by capturing contextual dependencies between biomedical entities to infer potential DDIs.
View Article and Find Full Text PDFOne Year Duration of Immune Response Following a 3rd Booster Dose of mRNA Vaccine Against COVID-19 in 292 Patients With Hematological Malignancies in University Hospital Ostrava, Czech Republic.
Cancer Med
December 2024
Department of Haemato-Oncology, University Hospital Ostrava, Ostrava, Czech Republic.
Aims: To evaluate antibody response to mRNA vaccine, identify subgroups with poor response and to determine long-term antibody durability in hematological patients.
Materials And Methods: We have vaccinated 292 patients with all hematological malignancies with a third dose of mRNA COMIRNATY vaccine with a 12-month follow-up period in our center in Ostrava, Czech Republic.
Results: Antibody response for the whole cohort exceeded 74% through the whole 12-month follow-up.
[Updates on hairy cell leukemia (HCL) and HCL-like disorders].
Bull Cancer
December 2024
Service d'hématologie, CHU de Poitiers, CIC 1402 Inserm université, 86000 Poitiers, France.
Hairy cell proliferations represent very different entities. They include hairy cell leukemia in its classic form (HCL), a well-defined entity, but also the variant form of HCL (LT-V ou HCL-V), whose presentation is far from HCL and whose prognosis is poorer. Other hairy cell proliferations include splenic red pulp lymphoma (SDRPL) and splenic marginal zone lymphomas (SMZL) with circulating villous cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!