BTK Inhibitor "Picture"

Bruton tyrosine kinase (BTK) inhibitor is a promising drug for the treatment of B-cell malignancies.
from the target to the approval of new drugs, it took about 20 years.
first-in-class drug Ibteni creates the possibility of a chemotherapy-free era for B-cell malignancies.
addition, clinical trials of a number of BTK inhibitors with anti-cancer potential have begun over the past 10 years, with more than 70 trials announced or updated in the last three years, with more follow-up data available.
, published October 29 in the journal Leukemia, summarizes important milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand their clinical and commercial potential.
source: Leukemia BTK consists of 659 amino acids and 5 domains: Pleckstrin homology (PH) domain, Tec homology (TH) domain, SRC homology 3 (SH3) domain, SH2 domain, and catalytic domain from N to C (Figure 1).
Figure 1. The BTK structure (source: Leukemia) PH domain binds to phosphatidyl inositol (e.g. PIP3) and collects proteins from the cell membrane.
TH domain contains a zinc finger sequence, which is important for the optimal activity and stability of proteins.
the SH domain to participate in protein-to-protein interactions and bind to tyrosine phosphorylase and proline-rich regions.
catalytic kinase domain Y551 bits can be LYN primary cancer gene (LYN) or spleen tyrosine kinase (SYK) phosphate, resulting in SH3 domain Y233 location of self-phosphate.
BTK is a key molecule that connects the BCR signal, the Toll-like subject (TLR) signal, and the tendon factor sensor signal (Figure 2).
in antigen-dependent BCR signals, the BTK can be activated by PI3K or SYK.
PI3K produces a necessary messenger PIP3 to activate the downstream path, which is often combined with BTK's PH domain, enabling SYK and LYN to activate BTK through full transphosphate at Y551 bits; XCL12, through the BTK and CXCR4 connection of heterogeneic tripolymer G protein sub-base direct interaction, combined with CXCR4 to induce BTK resuscing, in the antigen non-dependent TLR signal, most TLR recruit MYD88 to respond to TLR ligand polysaccharides.
BTK can interact directly with 5 different molecules to promote cell proliferation, antibody secretion, switch recombination and the production of inflammatory cytokines.
Figure 2. A diagram of the BTK in the BCR signal, TCR signal, and the tendon-factor sensor signal path.
BTK is an important component of antigen-dependent BCR signals that regulate B cell proliferation and survival.
addition, BTK also participates in antigen non-dependent Toll-like sensor signal transducting and degenerative factor sensor signal transducting, regulating B-cell adhesion, migration, and tumor microenvironmental forces.
(Source: Leukemia) Given BTK's key role in regulating B cells, it is naturally an attractive therapeutic target for autoimmune diseases and B-cell malignancies.
B cell malignancies include non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), the most common subtypes are chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), fable lymphoma (FL), multiple myeloma (MM), marginal lymphoma (MZL), cladding lymphoma (MCL) and WLA
NHL is the third-largest adaptive Chinese mainland trials of new drugs from 2009 to 2018.
it is worth noting that B-cell malignancies are among the most successful clinical trials in cancer.
NHL, MM and CLL have a probability of success from Phase I trials to FDA approval, respectively, to 8.5%, 9.7% and 7.3%, while the overall success rate of solid tumors is 5.7%.
, the treatment of malignant tumors in the B lymphatic system has made tremendous progress over the past 20 years and has greatly improved the prognostication of patients, especially in frail older patients.
BTK inhibitors are a new drug for the NHL.
since the structure and function of BTK were well defined in 1993, industry and academia have conducted extensive research to develop BTK inhibitors as anti-tumor or other drugs (Figure 3).
Figure 3. Key milestones in target discovery and clinical development of BTK inhibitors.
(Source: Leukemia) Ibtinib is the first effective selective BTK inhibitor approved by the FDA as a breakthrough therapy in 2013.
its approval is epoch-making.
Ibdinib was approved, toxic chemotherapy was the primary option for CLL/SLL, which brought with it the concept of no chemotherapy treatment for B-cell malignant tumors.
, the second generation of BTK inhibitors Akatini and Zebtinib were approved in 2017 and 2019, respectively, to reduce off-target effects.
Over the past 10 years, many preclinical and clinical studies have evaluated the efficacy of BTK inhibitors as a single drug or in combination with other standard chemotherapy, immunotherapy, or targeted drugs to treat a variety of cancers to broaden the market for adaptation.
history and characteristics of the discovery of BTK inhibitors Ibtinib is BTK's first-in-class inhibitor.
treatment of B-cell lymphoma with ibutoni was first reported by Honigberg L.A. et al.
results showed that oral ibtinib induced three responses in eight spontaneous B-cell non-Hodgkin's lymphoma model dogs.
, some selective second-generation BTK inhibitors were developed to overcome the off-target side effects and drug resistance of Ibteni.
ACP-196 is a second-generation BTK inhibitor designed by Aperta Pharma.
similar to Ibdinib, Harrington B.K. and others chose the dog B-cell NHL model to evaluate the effects of akatinib's in vitro medicine.
studies have shown that acatinib significantly inhibits the activation of BTK, thereby inhibiting the proliferation of CLBL1 in canine B-cell lymphoma cell line.
orR was 25% overall and the medium PFS for 20 dogs was 22.5 days.
(BGB-3111) is the next-generation BTK inhibitor developed by BeiGene in 2012.
The synthetic compound 31a has high potency, selectivity, introphysics properties, and good pharmacodynamic research in the OCI-LY10 DLBCL allogeneic transplantation model, and has been selected as a potential candidate drug.
the three approved BTK inhibitors have the same and different points as shown in Table 1: all inhibitors are combined with the 481-bit cysteine in BTK's ATP binding pocket in an irreversible co-price; According to biochemical binding dynamics, Ibteinib is the most effective BTK inhibitor, followed by Zebtini and Akatini;
1. Comparison of the characteristics and properties of Ibdini, Akatini and Zebtini.
in clinical applications, differences in pharmacodynamics and pharmacodynamics may affect the dose, efficiency, and adverse events of inhibitors.
The half-life of acatinib is shorter than that of ibtinib, which is given twice a day, and the share of BTK given twice a day is higher than that of once a day (95.3% vs 87.6%), which means that the drug needs to be given twice a day.
for zebtinib, persistent total inhibition (over 95% BTK occupancy in the lymph nodes) was more frequent in the 160 mg 2 times daily group than in the 320 mg daily group.
, choose 160 mg twice daily as the recommended dose for further study.
between rapid absorption and rapid elimination can lead to rapid target suppression and reduce the potential risk of off-target problems or drug interactions.
acatinib's shorter half-life and selective properties allow it to suppress BTK completely and continuously without increasing the toxic effects of selective kinase inhibition.
full-target coverage reduces drug resistance caused by BTK enzyme mutations and also reduces Richter conversion rates.
addition, although the three inhibitors have some different ideolytes in-body, whether these differences translate into clinical benefits and which BTK inhibitors are best-in-class drugs remains to be seen in subsequent head-to-head randomized clinical trials.
The latest clinical trials and follow-up results of BTK inhibitors in blood malignancies in MCL Advances In primary MCL cell lineages and tissues, some kinases such as SYK, PI3K, LYN and BTK are highly over-expressed and associated with NF-B activity, thus promoting the proliferation of MCL cells.
Ibtinib reduces activity, as well as damaged CXCR4 or CXCR5 mediator external adhesion and migration.
blocking the BCR signal is a promising method for MCLs.
Table 2-1. In terms of clinical advances in clinical studies of BTK inhibitors in MCLs, Advani et al. reported on a Phase I study in which Ibtini induced responses in 7 of the 9 patients with refroutable or recurring (R/R) MCL and identified 560 mg as the recommended Phase II study dose.
PCYC-1104 has shown that Ibtinib is less toxic and more effective than existing intensive chemotherapy options such as ESHAP, MINE, hyperCVAD and R-ICE.
based on this study, in 2013 Ibdinib was accelerated by the FDA for treatment of R/R MCL.
a randomized RAY study confirmed that Ibtinib was superior to ticiromos in 280 R/R MCL patients.
in R/R MCL, Ibutoni (66%) had higher ORR than other single-drug chemotherapy-free therapies, such as boronitazome (33%), lynadamine (28%), tysiromos (47%), otoxone monoanti (8%), and Ottoju monoantigen (27%) and Adelani (40%), which created the possibility of an MCL-free era of chemotherapy-free treatment.
, mortality and resistance increased significantly in MCL patients who did not achieve full remission (CR) after first-line treatment.
in long-term follow-up, the CR rate for single doses of Ibudinib in MCL was 20%, while the two-year PFS and OS rates were 79% and 92%, respectively, for patients who received CR using Ibdinib.
evidence will encourage Ibdinib to be combined with other treatment options to maximise CR rates.
BTK inhibitors advance in CLL/SLL In CLL cells, phosphorylation and activation of LYN, SYK, PKC beta, BTK, and PI3K can interact with microencient stimuli to initiate or maintain the survival, proliferation, or migration of CLL cells.
with regard to the dynamic interaction between CLL cells and their microentastic environment, macrophages in lymphatic organs exhibit M2-like esophageals to maintain the survival and proliferation of CLL cells, which Ibdinib may disrupt.
Zebutini also induces beneficial changes in the immune microencase by improving T-cell failure and reducing the adhesion/home-nesting inhibitors on checkpoint molecules on inhibited cells and on B cells.
results suggest that BTK inhibitors have an important effect on the malignant microencase of B cells.
Table 2-2. Clinical advances in clinical studies of BTK inhibitors in CLL/SLL Clinically, a combined analysis of PCYC-1102 and PCYC-1112 showed that patients receiving Ibudinib as a first-line treatment and those without large tumors were more likely to have CR after treatment, and that patients with R/R who received less prior treatment had longer medians of PFS and OS.
Del 17p or TP53 mutations have been shown to be less sensitive to classical immuno-chemotherapy, leading to early recurrence and short survival.
the RESONATE-17 trial and Ahn et al. paid particular attention to this sub-group and demonstrated that Ibteni performed well in CLL/SLL and was not affected by therapeutic history or genomic characteristics.
first-line Ibdinib drugs have also been tried by clinicians.
Ibtinigate fluorodarabin-cyclophosphamide-rituximab (fludarabine-cyclophosphamide-rituximab, FCR) showed 96% ORR and 36% CR or CRi.
iLLUMINATE test showed that the medium PFS of the chemotherapy-free Ibutinib-Ottoju monoantigenic solution was significantly longer than the benzodiazepine nitrogen mustard-Otto-pearl monoantigen.
April 21, 2020, the FDA approved Ibtinib/rituximab (ibrutinib/rituximab, IR) for the treatment of naive CLL/SLL in accordance with Phase III E1912 trial, which compared the efficacy of IR with the standard chemotherapy FCR.
in the study of BTK inhibitors in WM is characterized by bone marrow-soaked lymphatic plasma cells secreting high levels of monoclonal immunoglobulin M.
In the past, anti-CD20 monoantitor monoantigen or combined therapy (e.g. lytoxides-cyclophosphamides- lysameson, lyxi monoanti-benzoestin, or lysoxi monoanti-borontzomi-disamissons) were commonly used in patients with weakness or immune complications.
, however, patients with high baseline IgM levels are susceptible to lysoxi monoantigen-related IgM effects, and patients inevitably become resistant to lysic monoigen resistance.