Irreversible Inhibitor Of Bruton Tyrosine Kinase Research Articles

Discovery of Reversible, Noncovalent Bruton's Tyrosine Kinase Inhibitors Targeting BTK C481S Mutation.

Bruton's tyrosine kinase (BTK) is a promising target for treatment of B-cell malignancies and autoimmune disorders. Application of first- and second-generation irreversible BTK inhibitors against various lymphomas and leukemia is well-known. Some clinical limitations, such as off-target toxicity and primary or acquired drug resistance mutations including BTK C481S have been observed for irreversible BTK inhibitors. Developing selective reversible, noncovalent BTK inhibitors is a suitable strategy to overcome drug resistance problems. Recent approval of pirtobrutinib by the FDA in 2023 stimulated research interests for developing noncovalent mutant selective BTK inhibitors. In this letter, we report the discovery of a novel series of 1H-pyrrolo-[2,3-b]-pyridine derivatives as novel, selective next-generation BTK inhibitors targeting the BTK C481S mutation. One of the best compounds of the series, compound 36 showed in vivo efficacy and induced tumor suppression (TGI up to 82%) in mutant BTKC481S mouse xenograft models.

Rilzabrutinib for the Treatment of Immune Thrombocytopenia.

Advancements in the understanding of ITP pathogenesis have led to significant improvements in disease management through the use of both traditional immunosuppressive strategies and novel targeted therapies. However, a subset of patients remains refractory to treatment or achieves only transient benefits, underscoring the need for alternative therapeutic approaches. Bruton's tyrosine kinase (BTK) inhibitors have emerged as a promising strategy for autoimmune cytopenias, including ITP, due to their ability to modulate key immune pathways. Rilzabrutinib, an oral, reversible BTK inhibitor, represents a novel therapeutic approach for ITP. Rilzabrutinib, an oral, reversible BTK inhibitor, offers a novel mechanism of action by preserving platelet aggregation while reducing macrophage-mediated platelet clearance, distinguishing it from irreversible BTK inhibitors. This review provides an updated and comprehensive analysis of the Phase 1/2 LUNA 2 trial and its long-term extension, contextualizing rilzabrutinib within the broader treatment landscape. We also offer a comparative assessment of other BTK inhibitors investigated for ITP and discuss rilzabrutinib's potential positioning relative to existing therapies, including thrombopoietin receptor agonists (TPO-RAs), rituximab, fostamatinib, and immunosuppressants. Results from the phase 1/2 LUNA 2 trial and its long-term extension demonstrated that Rilzabrutinib induced a durable platelet response in 40% of patients, with a median time to response of 11.5 days. The treatment exhibited a favorable safety profile, with predominantly grade 1 or 2 adverse events and no significant safety concerns commonly associated with BTK inhibitors, such as increased bleeding risk, hepatic toxicity, or cardiac arrhythmias. Preliminary data presented at ASH 2024 from the ongoing Phase 3 LUNA 3 trial, a randomized, double-blind study, further support rilzabrutinib's efficacy and long-term safety. If confirmed, these findings suggest that rilzabrutinib could represent a valuable therapeutic option for patients with refractory ITP, addressing a critical unmet need and potentially redefining treatment paradigms.

Recent Progress of Irreversible BTK Inhibitors

In recent years, Bruton tyrosine kinase (BTK) inhibitors that selectively inhibit B cell receptor (BCR) signaling have become a popular and effective treatment for lymphomas in the public. As the pivotal tyrosine kinase BTK regulates the BCR pathway, BTK inhibitors were developed to block the pathway by binding with BTK thereby relieving the B-cell lymphoma progression. Ibrutinib, the first-generation BTK inhibitor, can effectively inhibit BTK and alleviate various cancer diseases. However, ibrutinib's lack of selectivity has led to a series of side effects, having adverse effects on survival rates and tolerability. By altering the molecular structure, researchers have developed the next-generation irreversible BTK inhibitors aiming at increasing target specificity and decreasing off-target impacts, such as acalabrutinib, tirabrutinib, spebrutinib, branebrutinib, and zanubrutinib, who recently received approval by FDA. This article compares and analyzes the advantages and disadvantages of these irreversible BTK inhibitors, especially zanubrutinib, with ibrutinib and finally draws a conclusion.

Phase 1 Study of TT-01488, a Novel, Non-Covalent, Reversible BTK Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies

Phase 1 Study of TT-01488, a Novel, Non-Covalent, Reversible BTK Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies

Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase.

scRNA-seq revealed characteristic gene expression patterns for MDSC from different patients with cancer and BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration.

A Phase 1 Study Evaluating PRT2527, a Potent and Highly Selective CDK9 Inhibitor, As Monotherapy and in Combination with Zanubrutinib in Patients with Select Relapsed/Refractory B-Cell Malignancies

A Phase 1 Study Evaluating PRT2527, a Potent and Highly Selective CDK9 Inhibitor, As Monotherapy and in Combination with Zanubrutinib in Patients with Select Relapsed/Refractory B-Cell Malignancies

Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Waldenström's Macroglobulinemia in a Single-Arm, Multicenter, Open-Label, Phase 2 Study: Long Term Follow-up Results

Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Waldenström's Macroglobulinemia in a Single-Arm, Multicenter, Open-Label, Phase 2 Study: Long Term Follow-up Results

Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib.

Bruton's tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. Ibrutinib is a first in class, covalent BTK inhibitor that limits B-cell survival and proliferation. Designing new inhibitors of BTK has been an important objective for advancing development of improved therapeutic agents against cancer and autoimmune disorders. Based on the success of Ibrutinib, several second-generation irreversible BTK inhibitors have been developed that exhibit fewer off-target effects. However, the binding-mode and their interaction with Btk have not been experimentally determined and evaluated at atomic resolution. Here we determined the first crystal structure of the BTK kinase domain in complex with acalabrutinib. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development.

A Pilot Study Evaluating Acalabrutinib for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphomas

A Pilot Study Evaluating Acalabrutinib for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphomas

Efficacy and Safety of Lenalidomide, Anti-PD-1 Antibody Combined with Orelabrutinib or Rituximab in the Treatment of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Efficacy and Safety of Lenalidomide, Anti-PD-1 Antibody Combined with Orelabrutinib or Rituximab in the Treatment of Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Thiotepa, Orelabrutinib, and Methotrexate Combined with or without the Rituximab Regimens in the Treatment of Patients with Central Nervous System Lymphoma

Thiotepa, Orelabrutinib, and Methotrexate Combined with or without the Rituximab Regimens in the Treatment of Patients with Central Nervous System Lymphoma

Novel 6-amino-1,3,5-triazine derivatives as potent BTK inhibitors: structure-activity relationship (SAR) analysis and preliminary mechanism investigation

Novel 6-amino-1,3,5-triazine derivatives as potent BTK inhibitors: structure-activity relationship (SAR) analysis and preliminary mechanism investigation

Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

Evaluation of orelabrutinib monotherapy in patients with relapsed or refractory Waldenström's macroglobulinemia in a single-arm, multicenter, open-label, phase 2 study.

Evaluation of orelabrutinib monotherapy in patients with relapsed or refractory Waldenström's macroglobulinemia in a single-arm, multicenter, open-label, phase 2 study.

Perioperative Bleeding Associated With Ibrutinib in Dermatologic Surgery: A Case-Control Study.

Ibrutinib, an irreversible Bruton tyrosine kinase inhibitor, has been associated with an increased risk of bleeding. There is a paucity of data on the risk of bleeding in patients on ibrutinib undergoing dermatologic surgery. To determine the frequency of bleeding complications associated with ibrutinib in patients undergoing dermatologic surgery. A retrospective, single-center, case-control study of patients on ibrutinib undergoing skin surgery between January 2013 and March 2020 compared with sex, disease, and age-matched control patients undergoing cutaneous surgeries. A total of 75 surgeries performed on 37 case patients and 116 surgeries performed on 64 control patients were included. Ibrutinib was associated with a statistically significant increased rate of bleeding events (6/75 [8%] vs 1/116 [0.8%], p -value = .02). Compared with ibrutinib patients who did not have a bleeding event, those on ibrutinib who suffered bleeding were all men, older (mean age 82.7 vs 73.0, p -value= .01), and had lower mean platelet counts (104.0 vs 150.5 K/μL, p -value = .03). Ibrutinib may be associated with increased risk of bleeding in patients with hematologic malignancies, particularly older men with lower platelet levels and on multiple anticoagulants. Transient discontinuation of ibrutinib should be considered for dermatologic surgeries.

Quantitative evaluation and pharmacokinetic characteristics of the irreversible BTK inhibitor zanubrutinib in mouse plasma using LC-MS/MS.

Zanubrutinib (BGB-3111) belongs to the class of irreversible inhibitors of Bruton's tyrosine kinase (BTK) for treating B-cell malignancies. A validated assay with excellent sensitivity, selectivity, and simplicity is required to measure plasma concentration and investigate its pharmacokinetics. The plasma of mice containing zanubrutinib and roxithromycin (internal standard) was processed with acetonitrile for protein precipitation. Then the supernatant was analyzed by high-performance liquid chromatography coupled with a triple quadrupole mass spectrometer using electrospray ionization in the positive mode. Zanubrutinib was given to mice intragastrically at 30 mg/kg to determine its pharmacokinetic parameters. The method was verified and showed good linearity in the range of 0.1-100 ng/mL. The method's sensitivity, accuracy, and precision were all within acceptable bounds. By this method, the pharmacokinetic profile of zanubrutinib in mouse plasma was measured.

Abstract 1400: AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK

Abstract Introduction: Bruton's tyrosine kinase (BTK) has been recently recognized as a validated drug target for the treatment of B-cell malignances. The emergence of clinical resistance to the first-generation covalent BTK inhibitors is, however, becoming a serious concern. Patients are reported to develop resistance during the treatment due to substitution of cysteine residue at position 481 with serine (C481S mutation) in BTK, which prevents the covalent binding of the first-generation irreversible BTK inhibitors, resulting in the loss of inhibitory activities. Therefore, there is a high unmet medical need for new therapeutic approaches to overcome the BTK C481S-mediated resistance. Material and methods: Compounds were tested in biochemical assays using recombinant human wildtype (WT) and C481S mutant BTKs. Cellular activity of AS-1763 was evaluated in human diffuse large B cell lymphoma (DLBCL) cell lines, OCI-Ly10 and its BTK[C481S] knock-in cells. The in vivo antitumor activity of AS-1763 was assessed in two tumor xenograft mouse models bearing WT or BTK [C481S] knock-in OCI-Ly10 cells. Results: We have discovered AS-1763 as an orally available, highly potent, selective and reversible BTK inhibitor. AS-1763 showed potent inhibitory activities for WT BTK (an activated form, BTK[A]) and the C481S mutant with sub-nanomolar IC50s (IC50 = 0.85 and 0.99 nM for BTK[A] and BTK[C481S], respectively). In cellular assays, AS-1763 exhibited strong antiproliferative activities for WT and BTK [C481S] knock-in OCI-Ly10 cells. AS-1763 demonstrated significant tumor growth inhibition and tumor regression in WT as well as BTK[C481S] knock-in OCI-Ly10 xenograft model. Conclusions: The preclinical data support the clinical development of AS-1763 in patients with B-cell malignancies both having WT and C481S mutation in BTK. The first-in-human Phase 1 clinical trial of AS-1763 in healthy volunteers (EudraCT 2020-005599-37) is currently ongoing, and the Phase 1b study in patients is expected to begin in 2022. Citation Format: Wataru Kawahata, Tokiko Asami, Takao Kiyoi, Takayuki Irie, Shigeki Kashimoto, Hatsuo Furuichi, Masaaki Sawa. AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1400.

Abstract CT532: Phase 1/2 results of ceralasertib (Cerala) as monotherapy or in combination with acalabrutinib (Acala) in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)

Abstract Introduction: Patients (pts) with CLL who relapse on therapies targeting B-cell receptor signaling pathways have limited treatment options. Cerala, a selective oral ATR inhibitor, has shown synergistic preclinical activity with a Bruton tyrosine kinase inhibitor (BTKi) in TP53- and ATM-defective CLL cells (Kwok et al. Blood. 2016;127:582-95). Acala is a selective, irreversible BTKi approved for CLL. This phase 1/2 proof-of-concept study investigated cerala alone and in combination with acala in high-risk R/R CLL. Methods: This multicenter, nonrandomized, open-label study (NCT03328273) enrolled adults with high-risk R/R CLL per iwCLL criteria and ECOG performance status ≤2. In Arm A, pts with TP53 mutation, del(17p), or del(11q) having exhausted available treatment options received cerala monotherapy (cohort 1: 160 mg BID continuously; cohort 2 [after ≥2 DLTs in cohort 1]: 160 mg BID 2 wk on/2 wk off). In Arm B, pts with del(11q) suitable for BTKi and cerala treatment per investigator judgment received acala 100 mg BID continuously alone for cycle 1 and acala 100 mg BID continuously + cerala 160 mg BID 1 wk on/3 wk off from cycle 2 onward. Primary objectives: safety and pharmacokinetics (PK). Secondary objective: activity—overall response rate (ORR), complete response rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Pharmacodynamic changes were explored using novel multiple reaction monitoring-targeted mass spectrometry. Results: Eleven pts were treated (median age 64 y; median prior therapy lines 3). Pts in Arm A (n=8 [7 received prior BTKi]: cohort 1 n=5; cohort 2 n=3) received cerala for a median of 3.5 mo (range 0.5-7.7). Grade (G) ≥3 AEs in >1 pt were anemia (75%), thrombocytopenia (63%), and neutropenia (25%); 4 DLTs of G4 thrombocytopenia were reported (3 in 2 pts in cohort 1; 1 in 1 pt in cohort 2). No responses were observed in Arm A. At a median follow-up of 15.1 mo, median PFS was 3.8 mo (95% confidence interval [CI] 0.7-4.6); median OS was 16.9 mo (95% CI 6.6-not reached [NR]). All pts had baseline telomeres within a “fusogenic” range (negative prognostic indicator).In Arm B (n=3; all BTKi-naive), 2 pts received acala + cerala and 1 received acala only. Median (range) treatment duration was 7.2 mo (4.9-9.5) for cerala and 15.9 mo (9.7-18.4) for acala. No G≥3 AEs or DLTs were reported. ORR was 100% (all partial responses); median DOR was NR. At a median follow-up of 15.9 mo, median PFS and OS were NR. PK of acala and cerala were consistent with historical data, with no drug-drug interactions when combined; cerala did not affect BTK occupancy. Conclusions: Cerala monotherapy in BTKi-exposed, high-risk CLL pts showed limited clinical benefit. Acala + cerala was tolerable with preliminary clinical activity in pts with CLL and del(11q). The study terminated due to the evolving treatment landscape. Citation Format: Wojciech Jurczak, Nagah Elmusharaf, Christopher P. Fox, William Townsend, Amanda G. Paulovich, Shringi Sharma, Graeme Parr, Veerendra Munugalavadla, Fanny Krantz, Helen Yang, Emma Dean, Richa Manwani, Peter Hillmen. Phase 1/2 results of ceralasertib (Cerala) as monotherapy or in combination with acalabrutinib (Acala) in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT532.

New Treatment Options for Newly-Diagnosed and Relapsed Chronic Lymphocytic Leukemia.

The better understanding of the biology of chronic lymphocytic leukemia (CLL) gained over the past decade has led to the development and introduction of several targeted drugs, with an demonstrable improvement in the prognosis for this currently incurable condition. Currently, Bruton's tyrosine kinase (BTK) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, venetoclax, and CD20 monoclonal antibodies are the key elements in the treatment of both previously untreated and relapsed/refractory CLL patients. Ibrutinib was the first BTK inhibitor approved for clinical use, and showed excellent efficacy and an acceptable safety profile. Following this, the better-tolerated second-generation irreversible BTK inhibitors acalabrutinib and zanubrutinib have been introduced for the treatment of lymphoid malignancies, and acalabrutinib was approved for CLL. When used as single drugs, BTK inhibitors are given continuously until unacceptable toxicity or disease progression; however, when combined with venetoclax and/or CD20 antibodies, they induce deeper response and can be given for a limited time. Recently, promising new reversible BTK inhibitors pirtobrutinib and nemtabrutinib were discovered, and these seem to be more active and better tolerated than their irreversible predecessors. However, they are in an early phase of development and are not currently approved for CLL. The phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib and duvelisib are highly effective in patients with relapsed CLL, including high-risk disease. The major limitations for their use are adverse events, mostly of autoimmune origin (hepatitis, enteritis/colitis, and pneumonitis). Otherwise, cellular therapies like allogeneic hematopoietic stem cell transplantation and chimeric antigen receptor (CAR) T cells and bispecific monoclonal antibodies offer promise for patients who have failed BTK inhibitors and venetoclax treatment. In the coming years, it is likely that novel targeted therapies will replace immunochemotherapy regimens in most patients.