Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 65(2), P. 1047 - 1131

Published: Oct. 8, 2021

The central role of dysregulated kinase activity in the etiology progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over past 40 years. As a result, inhibitors are today one most important classes drugs. FDA approved 73 small molecule inhibitor drugs until September 2021, and additional were by other regulatory agencies during that time. To complement published literature clinical inhibitors, we have prepared review recaps this large data set into an accessible format for medicinal chemistry community. Along with therapeutic pharmacological properties each across world 2020, provide synthesis routes originally used phase, many which only available patent applications. In last section, also update 2021.

Language: Английский

---

Small molecule inhibitors targeting the cancers

MedComm, Journal Year: 2022, Volume and Issue: 3(4)

Published: Oct. 13, 2022

Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary therapies for cancer. Due to their advantages a wide range targets, convenient medication, ability penetrate into central nervous system, many efforts have been devoted developing more small inhibitors. To date, 88 approved by United States Food Drug Administration treat cancers. Despite remarkable progress, cancer treatment still face obstacles, such as low response rate, short duration response, toxicity, biomarkers, resistance. better promote development targeting cancers, we comprehensively reviewed involved all agents pivotal drug candidates clinical trials arranged signaling pathways classification We discussed lessons learned from these agents, proper strategies overcome resistance arising different mechanisms, combination concerned Through our review, hoped provide insights perspectives research treatment.

Language: Английский

---

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Oct. 1, 2022

Bruton's tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid proliferation, survival, functions, making it a promising therapeutic target for various malignancies inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy been approved to treat different types hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib. The first-in-class agent, has created new era chemotherapy-free treatment malignancies. Ibrutinib so popular became the fourth top-selling cancer drug worldwide in 2021. To reduce off-target effects overcome acquired resistance significant efforts made developing highly selective second- third-generation BTK combination approaches. Over past few years, also repurposed Promising data obtained from preclinical early-phase clinical studies. In this review, we summarized current progress applying disorders, highlighting available results

Language: Английский

---

Cryo-EM structure of the human IgM B cell receptor

Science, Journal Year: 2022, Volume and Issue: 377(6608), P. 875 - 880

Published: Aug. 19, 2022

The B cell receptor (BCR) initiates immune responses through antigen recognition. We report a 3.3-angstrom cryo-electron microscopy structure of human immunoglobulin M (IgM)-BCR in the resting state. IgM-BCR comprises two heavy chains, light and Igα/Igβ heterodimer. ectodomains chains closely stack against those Igα/Igβ, with one chain locked between Igα Igβ juxtamembrane region. Extracellular interactions may determine isotype specificity BCR. transmembrane helices form four-helix bundle that appears to be conserved among all BCR isotypes. This contains 14 glycosylation sites on reveals three potential surface binding sites. Our work organizational principles facilitate design antibody-based therapeutics.

Language: Английский

---

Bruton’s Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials

Molecules, Journal Year: 2023, Volume and Issue: 28(5), P. 2400 - 2400

Published: March 6, 2023

In the last few decades, there has been a growing interest in Bruton’s tyrosine kinase (BTK) and compounds that target it. BTK is downstream mediator of B-cell receptor (BCR) signaling pathway affects proliferation differentiation. Evidence demonstrating expression on majority hematological cells led to hypothesis inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias lymphomas. However, body experimental clinical data demonstrated significance BTK, not just malignancies, but also solid tumors, breast, ovarian, colorectal, prostate cancers. addition, enhanced activity correlated with autoimmune disease. This gave rise beneficial therapy rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren’s syndrome (SS), allergies, asthma. this review article, we summarize most recent findings regarding well advanced have developed date their applications mainly cancer chronic inflammatory disease patients.

Language: Английский

---

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

Cancers, Journal Year: 2022, Volume and Issue: 14(3), P. 771 - 771

Published: Feb. 2, 2022

The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) reversible (non-covalent) inhibitors. Ibrutinib was first inhibitor approved by U.S. Food Drug Administration in 2013 as breakthrough therapy CLL patients. Subsequently, several studies have evaluated efficacy safety new agents reduced toxicity when compared ibrutinib. Two other irreversible, second-generation inhibitors, acalabrutinib zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, currently under development early-phase improve their activity diminish This review summarizes pharmacology, efficacy, safety, dosing, drug–drug interactions associated treatment examines further implications.

Language: Английский

---

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(10), P. 2807 - 2807

Published: May 16, 2022

The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects antigen receptor (BCR) signaling. (BTKis) are classified into three categories, namely covalent irreversible inhibitors, reversible and non-covalent inhibitors. Ibrutinib first covalent, inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other irreversible, second-generation BTKis, acalabrutinib zanubrutinib, have been developed malignancies to reduce ibrutinib-mediated adverse effects. More recently, BTKis under development immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, spontaneous urticaria, among others. This review article summarizes preclinical clinical evidence supporting role various autoimmune, allergic, inflammatory conditions.

Language: Английский

---

Evidence-based expert consensus on the management of primary central nervous system lymphoma in China

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Sept. 29, 2022

Abstract Primary central nervous system lymphoma (PCNSL) is a type of restricted non-Hodgkin lymphoma, whose histopathological diagnosis majorly large B cell lymphoma. To provide specific, evidence-based recommendations for medical professionals and to promote more standardized, effective safe treatment patients with PCNSL, panel experts from the Chinese Neurosurgical Society Medical Association Hematological Malignancies Anti-Cancer jointly developed an consensus. After comprehensively searching literature conducting systematic reviews, two rounds Delphi were conducted reach consensus on as follows: The specimens PCNSL should be obtained safely possible by multimodal tomography-guided biopsy or minimally invasive surgery. Corticosteroids withdrawn from, not administered to, suspected before if patient’s status permits. MRI (enhanced DWI) performed diagnosing evaluating where whole-body PET-CT used at necessary time points. Mini-mental examination can assess cognitive function in clinical management. Newly diagnosed treated combined high-dose methotrexate-based regimen rituximab-inclusive induction therapy. Autologous stem transplantation consolidation Refractory relapsed ibrutinib without chemotherapy re-induction Stereotactic radiosurgery limited recurrent lesion who refractory have previously received whole-brain radiotherapy. Patients primary vitreoretinal (PVRL) vitreous biopsy. PVRL concurrent VRL systemic local

Language: Английский

---

Next Generation BTK Inhibitors in CLL: Evolving Challenges and New Opportunities

Cancers, Journal Year: 2023, Volume and Issue: 15(5), P. 1504 - 1504

Published: Feb. 27, 2023

Ibrutinib revolutionized the CLL treatment approach and prognosis demonstrating its efficacy safety even at extended follow-up. During last few years, several next-generation inhibitors have been developed to overcome occurrence of toxicity or resistance in patients on continuous treatment. In a head-to-head comparison two phase III trials, both acalabrutinib zanubrutinib demonstrated lower incidence adverse events respect ibrutinib. Nevertheless, mutations remain concern with therapy were first- covalent inhibitors. Reversible showed independently previous presence BTK mutations. Other strategies are currently under development CLL, especially for high-risk patients, include inhibitor combinations BCl2 without anti-CD20 monoclonal antibodies. Finally, new mechanisms inhibition investigations progressing non-covalent Here we summarize discuss results from main experiences irreversible reversable CLL.

Language: Английский

---

From development to clinical success: the journey of established and next-generation BTK inhibitors

Investigational New Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Language: Английский

---