Medicinal Chemistry Strategies for the Development of Bruton’s Tyrosine Kinase Inhibitors against Resistance

Abstract

Despite significant efficacy, one of the major limitations of small-molecule Bruton’s tyrosine kinase (BTK) agents is the presence of clinically acquired resistance, which remains a major clinical challenge. This Perspective focuses on medicinal chemistry strategies for the development of BTK small-molecule inhibitors against resistance, including the structure-based design of BTK inhibitors targeting point mutations, e.g., (i) developing noncovalent inhibitors from covalent inhibitors, (ii) avoiding steric hindrance from mutated residues, (iii) making interactions with the mutated residue, (iv) modifying the solvent-accessible region, and (v) developing new scaffolds. Additionally, a comparative analysis of multi-inhibitions of BTK is presented based on cross-comparisons between 2916 unique BTK ligands and 283 other kinases that cover 7108 dual/multiple inhibitions. Finally, targeting the BTK allosteric site and uding proteolysis-targeting chimera (PROTAC) as two potential strategies are addressed briefly, while also illustrating the possibilities and challenges to find novel ligands of BTK.

Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton’s Tyrosine Kinase

“…A similar procedure was used for the U87MG xenografts in which NOD SCID mice were injected with 5 × 10 6 U87MG cells (0.1 mL 1:1 Matrigel/PBS). After 17 days, the tumor volume reached around 172−221 mm 3 , and the mice were used for imaging experiments.…”

“…1,2 Dysregulation of BTK signaling occurs in various B-cell malignancies, and BTK is a target for treating diseases such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). 3,4 BTK is also a target for treating autoimmune diseases, and BTK inhibitors have been effective in animal models of lupus and rheumatoid arthritis (RA). 5−7 Several BTK inhibitors have been approved for the treatment of B-cell-related hematologic malignancies, including ibrutinib, 8 acalabrutinib, 9,10 zanubrutinib, 11 tirabrutinib, 12 and orelabrutinib.…”

“…Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase that plays a critical role in the B-cell receptor (BCR) signaling pathway. , Dysregulation of BTK signaling occurs in various B-cell malignancies, and BTK is a target for treating diseases such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). , BTK is also a target for treating autoimmune diseases, and BTK inhibitors have been effective in animal models of lupus and rheumatoid arthritis (RA). − Several BTK inhibitors have been approved for the treatment of B-cell-related hematologic malignancies, including ibrutinib, acalabrutinib, , zanubrutinib, tirabrutinib, and orelabrutinib . However, BTK inhibitors for autoimmune diseases including RA, lupus, and multiple sclerosis (MS) have not yet been approved, and there is an unmet need to better understand the role of BTK in cancer and autoimmune diseases in order to develop more effective BTK inhibitors for these diseases …”

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

“…Step B: N-((1S,2R)-2-Aminocyclopentyl)acrylamide (19). To a solution of tert-butyl ((1R,2S)-2-acrylamidocyclopentyl)carbamate (800 mg, 3.146 mmol) in DCM (20 mL) was added methanesulfonic acid (1.208 g, 12.58 mmol) and was stirred at room temperature for 30 min.…”

“…Three covalent BTK inhibitors, ibrutinib, acalabrutinib, and zanubrutinib, have been approved for the treatment of hematologic malignancies, and additional covalent BTK inhibitor chemotypes have been reported. − Despite the success of these drugs, the treatment of hematological malignancies with BTK inhibitors as monotherapies remains challenging due to a substantial proportion of patients not achieving complete response or experiencing relapse . Therefore, additional highly selective, efficacious, and safe BTK inhibitors are needed to achieve transformational efficacy with combination therapies.…”