HDAC6 Selective Inhibitors Combined with BTK Inhibitors for CLL
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Solution Overview
Problem
Current treatments for chronic lymphocytic leukemia (CLL) using HDAC inhibitors are limited by non-selectivity and undesirable side effects, and BTK inhibition only achieves partial responses with relapse, necessitating the development of more effective and permanent therapeutic strategies.
Innovation Solution
The use of HDAC6 selective inhibitors, such as compounds of Formula I, II, A, B, C, and D, in combination with BTK inhibitors like ibrutinib, to target CLL cells, reduce viability, alter expression of inhibitory checkpoint molecules, decrease IL-10 expression, and inhibit proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pan-HDAC inhibitors are used to treat CLL, then antileukemic activity is induced, but non-selectivity causes undesirable side effects
Solution Approach 1:
The patent segments the HDAC inhibitor class into iso-selective inhibitors targeting specific HDAC isoforms (HDAC1, HDAC2, HDAC3, HDAC6, or HDAC8) rather than using pan-HDAC inhibitors. This segmentation allows selective inhibition of specific HDAC isoforms involved in CLL pathogenesis while sparing other isoforms, thereby maintaining antileukemic activity while reducing non-selectivity-related side effects
Solution Approach 2:
The patent applies local quality by designing HDAC inhibitors with specific molecular structures (compounds of Formula I and Formula II) that exhibit preferential binding to particular HDAC isoforms. This localized selectivity ensures that only specific HDAC isoforms expressed in CLL cells are inhibited, while other isoforms in healthy tissues remain unaffected, thus reducing systemic side effects
2Reliability
If BTK inhibitors are used to treat CLL, then proliferation is blocked and apoptosis is increased, but only partial responses are achieved and relapse occurs
Solution Approach 1:
The patent merges BTK inhibition with iso-selective HDAC inhibition in a combination therapy regimen. This combination targets two distinct molecular pathways: BTK signaling and HDAC-mediated epigenetic regulation. The synergistic effect of dual targeting achieves more complete and durable responses compared to monotherapy, preventing relapse by simultaneously blocking proliferation signals and inducing apoptosis through epigenetic modulation
Solution Approach 2:
The patent employs a composite therapeutic approach combining two different mechanism-of-action agents (BTK inhibitor and iso-selective HDAC inhibitor). This composite therapy strategy creates a more robust and sustained antileukemic effect by engaging multiple molecular pathways, thereby extending the duration of response and reducing relapse rates compared to single-agent therapy
3Adaptability or versatility
If HDAC6 selective inhibitors are used, then immunomodulatory molecule expression is altered, but mechanism of action in CLL is under investigation
Solution Approach 1:
The patent incorporates feedback mechanisms by monitoring changes in immunomodulatory molecule expression (such as PD-L1, PD-L2, CTLA-4) as biomarkers of HDAC6 inhibitor response. This feedback allows for assessment of therapeutic efficacy and mechanistic insight into how HDAC6 inhibition modulates the immune microenvironment in CLL, progressively building reliable mechanistic understanding through observable molecular changes
Data Source
AI summary
Disclosed are histone deacetylase (HDAC) inhibitors, or combinations comprising an HDAC inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of chronic lymphocytic leukemia in a subject in need thereof. Also provided herein are methods for treating chronic lymphocytic leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an HDAC inhibitor, or a combination comprising an HDAC inhibitor and a BTK inhibitor. Other related methods are disclosed.