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Ref Type Abstract
PMID
Authors Yu Bai, Ting Wu, Minghui Hu, Sufang Han, Yu Liu, Jie Zheng, Junjun Qin, Lin Zhang, Zhenfan Yang
Title Preclinical Study of DZD8586, a Non-Covalent LYN/BTK Dual Inhibitor with Excellent BBB Penetration, for the Treatment of B-Cell Non-Hodgkin Lymphoma (B-NHL)
Journal Vol Issue Date Pages Journal Short Title
Blood 142 Supplement 1 November 2, 2023 2822 Blood
URL https://ashpublications.org/blood/article/142/Supplement%201/2822/500345/Preclinical-Study-of-DZD8586-a-Non-Covalent-LYN
Abstract Text Bruton's Tyrosine Kinase (BTK) inhibitors have been approved for the treatment of B-NHL, such as CLL and MCL. However, resistance to BTK inhibitors still inevitably occurred, and different types of mutations were identified post covalent and non-covalent BTK inhibitor treatment. Although BTK inhibitors showed some activities in the treatment of relapsed or refractory non-germinal center B-cell (non-GCB) DLBCL, no drugs have been approved due to unsustainable tumor response. It is hypothesized that blockage of BTK pathway alone is not sufficient to achieve optimal anti-tumor efficacy in DLBCL. Due to limited blood-brain barrier (BBB) penetration of the current therapies, treatment of central nervous system lymphoma (CNSL) remains a clinical challenge. DZD8586 is a rationally designed, oral, non-covalent, LYN and BTK dual inhibitor with excellent BBB penetration as a potential treatment option for B-NHL. Here we report the preclinical activity of DZD8586 in lymphoma cell lines and animal models which supports its clinical development to address the above unmet medical needs. Methods The enzymatic activity of DZD8586 against multiple kinases was assessed at Eurofins panel with purified enzymes. TMD-8-IbruR cells carrying the C481S mutation were generated by stepwise induction of increasing concentrations of Ibrutinib. Cells carrying pirtobrutinib resistance mutations were obtained by transfection of different BTK mutations into RI-1 cells using lentivirus. Cell growth inhibition was determined by CellTiter-Glo. A pBTK enzyme-linked immunosorbent assay (ELISA) was used to evaluate the pharmacodynamic profile of DZD8586. Western blot was used to test the modulations of signaling pathways with DZD8586 treatment. Animal models were established by subcutaneous and intracranial inoculation of tumor cells, respectively, and animals were treated with DZD8586 or other BTK inhibitors. The anti-tumor efficacy was assessed by comparing the change in mean tumor volume between the different treatment groups and vehicle controls. Results Kinase panel profiling showed that DZD8586 potently inhibited LYN and BTK, with good selectivity against other kinases. In cell lines expressing C481X and pirtobrutinib resistance mutations, DZD8586 demonstrated concentration dependent anti-proliferative effects, with similar GI 50s among cells carrying different BTK mutations. In a panel of DLBCL cell lines, DZD8586 exhibited potent cell growth inhibition and induced cell death in a variety of cell lines, and its effect correlated with modulations of both LYN and BTK pathways. In both subcutaneous and CNS tumor models, DZD8586 exhibited profound tumor growth inhibition in a dose-dependent manner, and induced tumor regression at the doses of 50 mg/kg and above. There was a good correlation between plasma concentrations of DZD8586 and modulations of pBTK in whole blood and tumor tissue. DZD8586 has good cell permeability and is not significantly transported by P-gp and BCRP expressed at the BBB. The K puu,CSF of DZD8586 in rat and monkey were 1.2 and 1.3, respectively, suggesting its excellent BBB penetration in humans. Conclusion DZD8586 is a novel non-covalent LYN/BTK dual inhibitor, which could overcome resistance mutations to the approved covalent and non-covalent BTK inhibitors, and derive clinical benefit to patients with DLBCL and CNSL by blocking both BTK-dependent and BTK-independent signaling pathways with excellent BBB penetration.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
DZD8586 DZD8586 8 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
DZD8586 DZD-8586|DZD 8586 BTK inhibitor 37 LYN Inhibitor 4 DZD8586 is a non-covalent inhibitor of BTK and LYN that is blood-brain barrier-penetrant, which potentially induces tumor cell death and decreases tumor growth (Blood (2023) 142 (Supplement 1): 2822).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK C481S lymphoma predicted - sensitive DZD8586 Preclinical - Cell culture Actionable In a preclinical study, DZD8586 inhibited proliferation of lymphoma cells expressing BTK C481S in culture (Blood (2023) 142 (Supplement 1): 2822). detail...
BTK A428D lymphoma predicted - sensitive DZD8586 Preclinical - Cell culture Actionable In a preclinical study, DZD8586 inhibited proliferation of lymphoma cells expressing BTK A428D in culture (Blood (2023) 142 (Supplement 1): 2822). detail...
BTK M437R BTK C481S lymphoma predicted - sensitive DZD8586 Preclinical - Cell culture Actionable In a preclinical study, DZD8586 inhibited proliferation of lymphoma cells expressing BTK M437R and BTK C481S in culture (Blood (2023) 142 (Supplement 1): 2822). detail...
BTK C481Y lymphoma predicted - sensitive DZD8586 Preclinical - Cell culture Actionable In a preclinical study, DZD8586 inhibited proliferation of lymphoma cells expressing BTK C481Y in culture (Blood (2023) 142 (Supplement 1): 2822). detail...
BTK L528W lymphoma predicted - sensitive DZD8586 Preclinical - Cell culture Actionable In a preclinical study, DZD8586 inhibited proliferation of lymphoma cells expressing BTK L528W in culture (Blood (2023) 142 (Supplement 1): 2822). detail...
BTK M437R lymphoma predicted - sensitive DZD8586 Preclinical - Cell culture Actionable In a preclinical study, DZD8586 inhibited proliferation of lymphoma cells expressing BTK M437R in culture (Blood (2023) 142 (Supplement 1): 2822). detail...
BTK C481F lymphoma predicted - sensitive DZD8586 Preclinical - Cell culture Actionable In a preclinical study, DZD8586 inhibited proliferation of lymphoma cells expressing BTK C481F in culture (Blood (2023) 142 (Supplement 1): 2822). detail...
BTK V416L lymphoma predicted - sensitive DZD8586 Preclinical - Cell culture Actionable In a preclinical study, DZD8586 inhibited proliferation of lymphoma cells expressing BTK V416L in culture (Blood (2023) 142 (Supplement 1): 2822). detail...