Contributions
Abstract: EP527
Type: E-Poster Presentation
Session title: Aggressive Non-Hodgkin lymphoma - Clinical
Background
It has been an on-demand task to develop a BTK inhibitor of significant brain exposure, a critical property for extending its usages to treat Primary Central Nervous System Lymphoma (PCNSL) and autoimmune disorders. PCNSL is an aggressive extra nodal non-Hodgkin lymphoma that exclusively invades the central nervous system (CNS). Tirabrutinib, an irreversible BTK inhibitor with limited brain exposure, is the first BTK inhibitor approved for the treatment of recurrent or refractory primary central nervous system lymphoma recently. PRN2246 is another irreversible BTK inhibitor claimed to be of brain exposure, and is currently in clinical trials for the treatment of multiple sclerosis.
Aims
Discovery of Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) with High Brain Exposure
Methods
New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further measured for brain exposures in rats.
Results
HBW-3-20 has excellent potency against both wild-type and C481S-mutated BTK, with IC50 of 2.5 and 3.8 nM, respectively. Its TMD8 cellular potency is 72 nM. In a head-to-head direct comparison of brain exposure experiment, HBW-3-20, tirabrutinib and PRN2246 were all dosed at 10mg/kg orally. The brain and plasma concentration were measured after 1 hour and the data are shown in the table below. The brain to plasma ratio for HBW-3-20, tirabrutinib and PRN2246 are 58%, 11.8% and 4.2% respectively. Our results show that HBW-3-20 has much greater brain permeability than tirabrutinib or PRN2246 in rats.
Compound | tirabrutinib | PRN-2246 | HBW-3-20 |
BTK IC50 (nM) | 22 | 2.1 | 2.5 |
BTKC481S IC50 (nM) | na | na | 3.8 |
TMD8 IC50 (nM) | 158 | 29 | 72 |
Plasma concentration（ng/mL） | 713 | 387 | 3457 |
Brain tissue concentration（ng/mL） | 84 | 16.5 | 2009 |
Brain/Plasma Ratio（%） | 11.8 | 4.2 | 58 |
Conclusion
HBW-3-20 is the first potent reversible BTK inhibitor with superior brain permeability. HBW-3-20 provides a very valuable clinical candidate for treating B-cell malignancies in brain and autoimmune disorders!
Keyword(s): Autoimmune disease, B cell chronic lymphocytic leukemia, B cell lymphoma, Inhibitor
Abstract: EP527
Type: E-Poster Presentation
Session title: Aggressive Non-Hodgkin lymphoma - Clinical
Background
It has been an on-demand task to develop a BTK inhibitor of significant brain exposure, a critical property for extending its usages to treat Primary Central Nervous System Lymphoma (PCNSL) and autoimmune disorders. PCNSL is an aggressive extra nodal non-Hodgkin lymphoma that exclusively invades the central nervous system (CNS). Tirabrutinib, an irreversible BTK inhibitor with limited brain exposure, is the first BTK inhibitor approved for the treatment of recurrent or refractory primary central nervous system lymphoma recently. PRN2246 is another irreversible BTK inhibitor claimed to be of brain exposure, and is currently in clinical trials for the treatment of multiple sclerosis.
Aims
Discovery of Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) with High Brain Exposure
Methods
New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further measured for brain exposures in rats.
Results
HBW-3-20 has excellent potency against both wild-type and C481S-mutated BTK, with IC50 of 2.5 and 3.8 nM, respectively. Its TMD8 cellular potency is 72 nM. In a head-to-head direct comparison of brain exposure experiment, HBW-3-20, tirabrutinib and PRN2246 were all dosed at 10mg/kg orally. The brain and plasma concentration were measured after 1 hour and the data are shown in the table below. The brain to plasma ratio for HBW-3-20, tirabrutinib and PRN2246 are 58%, 11.8% and 4.2% respectively. Our results show that HBW-3-20 has much greater brain permeability than tirabrutinib or PRN2246 in rats.
Compound | tirabrutinib | PRN-2246 | HBW-3-20 |
BTK IC50 (nM) | 22 | 2.1 | 2.5 |
BTKC481S IC50 (nM) | na | na | 3.8 |
TMD8 IC50 (nM) | 158 | 29 | 72 |
Plasma concentration（ng/mL） | 713 | 387 | 3457 |
Brain tissue concentration（ng/mL） | 84 | 16.5 | 2009 |
Brain/Plasma Ratio（%） | 11.8 | 4.2 | 58 |
Conclusion
HBW-3-20 is the first potent reversible BTK inhibitor with superior brain permeability. HBW-3-20 provides a very valuable clinical candidate for treating B-cell malignancies in brain and autoimmune disorders!
Keyword(s): Autoimmune disease, B cell chronic lymphocytic leukemia, B cell lymphoma, Inhibitor