Medically reviewed by Dr. Brian Koffman
The Bottom Line:
Preclinical research shows that LP-168 inhibits BTK in CLL cells regardless of whether resistance mutations exist. Clinical trials testing this compound are currently underway.
Who Performed the Research and Where Was it Presented:
Dr. Britten Gordon from the Ohio State University and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023. Dr. Brian Koffman spoke with Dr. Adam Kittai about this research.
Background:
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) cells rely on the enzyme Bruton tyrosine kinase (BTK) for their survival and proliferation. Because of this, BTK inhibitors have successfully treated CLL / SLL, and several types of BTK inhibitors have been developed.
Ibrutinib was the first BTK inhibitor to be approved for CLL, and it was followed by the second-generation BTK inhibitors acalabrutinib and zanubrutinib, which are more specific and safer. All of these are covalent BTK inhibitors that irreversibly bind to a specific site on the BTK protein and inhibit its function. However, over time, patients can develop resistance mutations at the C481S site on BTK, which is where covalent BTK inhibitors bind.
This led to the development of pirtobrutinib, a noncovalent BTK inhibitor that binds reversibly to BTK and can extend the benefits of BTK in patients who are resistant to covalent BTK. However, patients can eventually develop resistance to non-covalent BTK inhibitors as well, so it is important to think about what treatments might come next.
Now, a new BTK inhibitor (LP-168) is in development that can bind to BTK both covalently and noncovalently.
Methods and Participants:
This preclinical study treated CLL cells in a dish with LP-168.
Results
- LP-168 is very selective for BTK, which should hopefully minimize off-target effects (effects on other proteins in the body).
- LP-168 inhibited the B cell receptor (BCR) signaling pathway and significantly reduced the activation of BTK and PLCG2.
- LP-168 caused the death of normal CLL cells as well as CLL cells carrying the C481S or T474I mutations (two of the major mutations involved in resistance to covalent and noncovalent BTK inhibitors).
Conclusion:
LP-168 is a selective dual covalent/noncovalent BTK inhibitor that works regardless of whether resistance mutations are present. It is currently being tested in a phase 1 clinical trial for patients with relapsed / refractory B cell cancers, including CLL / SLL. If you are interested in participating, more information can be found here: Study of Oral Administration of LP-168 in Patients With Relapsed or Refractory B-cell Malignancies.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Targeting Covalent and Non-Covalent Btki-Resistant CLL Using the Dual Irreversible/Reversible 4th Generation BTK Inhibitor LP-168.
Take care of yourself first.
Ann Liu, PhD
