Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g.

Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance.

Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase for B-Cell Malignancies and Autoimmune Diseases.

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (-) leads to a series of highly selective BTK inhibitors, in which - is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.

Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds.

Synthesis and biological evaluation of one novel technetium-99m-labeled nitroquipazine derivative as an imaging agent for serotonin transporter.

Imaging of serotonin transporter (SERT) by positron emission tomography (PET) or single-photon emission-computed tomography (SPECT) in humans would provide useful information in diagnosis and therapy of several neurodegenerative and neuropsychiatric disorders. 6-Nitroquipazine is a highly potent and selective inhibitor of the SERT. For the development of new (99m)Tc-labeled 6-nitroquipazine derivatives as SERT imaging agents, novel [N-[2-((3-(4-(6-nitroquinolin-2-yl)piperazin-1-yl)propyl)(2-mercaptoethyl)amino]-acetyl-2-aminoethanethiolato] [(99m)Tc]technetium (V) oxide ((99m)Tc-MAMA-3-PQ) and its rhenium analog were synthesized and characterized.

Caution to HPLC analysis of tricarbonyl technetium radiopharmaceuticals: an example of changing constitution of complexes in column.

Radio-HPLC is a powerful tool for analyzing radioactive species in radiopharmaceutical chemistry. In this paper, we found an example that the commonly used eluting solvent, acetonitrile, could coordinate with the popular radiopharmaceutical nuclides, technetium-99m, during chromatography. [(99m)Tc(CO)(3)(H(2)O)(3)](+) and [Re(CO)(3)(H(2)O)(3)](+) showed quite different retention time when they were eluted using acetonitrile/water as mobile phase.