Use of CDK9 and BRD4 inhibitors to inhibit inflammation
Inventors
Haudenschild, Dominik • Yik, Jasper
Assignees
University of California Davis • University of California San Diego UCSD
Publication Number
US-11020404-B2
Publication Date
2021-06-01
Expiration Date
2035-10-13
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Abstract
Provided are methods for the combined use of cyclin-dependent kinase 9 (CDK9) inhibitors and bromodomain containing 4 (BRD4) inhibitors to reduce, inhibit and/or prevent cartilage degradation and systemic traumatic inflammation. A combination of CDK9 inhibitors and BRD4 inhibitors can be used to reduce, inhibit and/or prevent cartilage degradation and loss of cartilage viability during allograft storage. A combination of CDK9 inhibitors and BRD4 inhibitors can be used as a post-injury intervention treatment to reduce, inhibit and/or prevent the acute cellular responses that lead to future cartilage degradation and osteoarthritis.
Core Innovation
The invention provides methods for the combined use of cyclin-dependent kinase 9 (CDK9) inhibitors and bromodomain containing 4 (BRD4) inhibitors to reduce, inhibit, or prevent cartilage degradation and systemic traumatic inflammation. The approach is based on the discovery that all inflammatory stimuli converge upon the combined activation of CDK9 and BRD4 for the transcriptional elongation of primary inflammatory response genes. By inhibiting transcriptional elongation through both CDK9 and BRD4, the method can broadly repress inflammatory gene expression without affecting housekeeping genes, thereby minimizing cellular or tissue harm in the short term.
The background identifies a critical challenge: conventional anti-inflammatory agents target individual cytokines or pathways, a strategy that is insufficient because systemic inflammatory response syndrome (SIRS) and trauma-induced inflammation involve multiple convergent and redundant pathways. Drugs targeting specific receptors or mediators fail to block the full spectrum of inflammatory responses, and no effective pharmacologic agents currently exist to prevent SIRS or significantly improve trauma outcomes. There is thus an urgent need for an approach that acts rapidly and universally across inflammatory triggers.
This invention addresses the problem by targeting the rate-limiting step controlled by CDK9 and its recruitment by BRD4. Pharmacological inhibition of CDK9 and BRD4 using agents such as flavopiridol (for CDK9) and JQ1 or GSK525762A (for BRD4) effectively suppresses the activation of primary inflammatory response genes in human articular chondrocytes and in tissue models. The combined use of these inhibitors can be administered systemically, locally, intravenously, or directly to injury sites in various dosing regimens, to reduce acute cellular responses, decrease inflammatory mediator production, and prevent the cascade of cartilage destruction or systemic inflammation that follows injury.
Claims Coverage
The claims present a single independent inventive feature centered on the synergistic use of CDK9 and BRD4 inhibitors to reduce inflammation, with various dependent claims specifying administration, compounds, dosing, and target tissues.
Synergistic reduction of inflammation by combination of CDK9 and BRD4 inhibitors
The main inventive feature is a method of treating or reducing inflammation in tissue by administering an effective amount of a combination comprising a CDK9 inhibitor or salt thereof and a BRD4 inhibitor or salt thereof, where the combination provides a synergistic reduction in an inflammation response as compared to either inhibitor alone. - The combination suppresses inflammatory responses in cells near or at the site of an injury, including traumatic injuries. - The combination is applicable to cells or tissues such as cartilage, chondrocyte, joint, synovial cell, meniscal cell, ligament, and bone. - The combination inhibits activation of catabolic pathways and reduces or inhibits transcriptional activation of primary response genes (including IL-1β, iNOS, COX2, IL-6, TNF-α, MMP-1, MMP-3, MMP-9, MMP-13, ADAMTS4). - Dosing regimens include administration within about 10 days, 1 to 4 days, or 3 hours of injury, and can be repeated or sustained. - The combination can reduce, delay, inhibit, or prevent future onset of osteoarthritis. - CDK9 inhibitors include flavopiridol, 4-(3,5-diamino-1H-pyrazol-4-ylazo)-phenol, 2-(pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridinone, and PHA-767491. - BRD4 inhibitors include JQ1 and GSK525762A. - Therapeutic outcomes include decreasing pain, decreasing swelling, and increasing joint mobility.
The inventive feature claimed is the synergistic use of CDK9 and BRD4 inhibitors, administered as a combination, to effectively reduce or inhibit inflammation and prevent downstream tissue degradation in trauma or injury, with broad applicability to joint and cartilage-related conditions.
Stated Advantages
The combination of CDK9 and BRD4 inhibitors suppresses inflammatory responses from all inflammatory stimuli, providing broader effectiveness compared to conventional approaches targeting individual cytokines or pathways.
Combined CDK9 and BRD4 inhibition reduces the necessary dosages of individual drugs, minimizing potential off-target effects.
This method does not affect housekeeping genes or basal gene expression, minimizing adverse effects on cells or tissues in the short term.
Rapid intervention with these inhibitors after injury can reduce or prevent acute inflammatory responses that lead to cartilage degradation and osteoarthritis.
Administration of the combination can decrease pain, swelling, and increase joint mobility.
The approach allows for longer storage life for osteochondral explants by preventing cartilage degradation during storage.
Documented Applications
Post-injury intervention treatment to reduce, inhibit, or prevent acute cellular responses leading to cartilage degradation and osteoarthritis.
Reduction, inhibition, or prevention of cartilage degradation and loss of cartilage viability during allograft storage.
Reduction, inhibition, or prevention of severe polytrauma or systemic inflammatory response syndrome (SIRS) following traumatic injury.
Suppression of inflammatory and catabolic events after joint or cartilage tissue trauma, including applications following surgery or osteochondral explant transplantation.
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