Harnessing the Ubiquitin Proteasome System to Block Inflammation
IRAK4 Degrader
Chronic inflammatory diseases such as rheumatoid arthritis (RA) represent an area of high clinical unmet need with global adult prevalence rates of about 1%. IRAK4 is a serine/threonine kinase that acts as a central mediator of TLR and IL-1R signaling and has emerged as a therapeutic target in multiple chronic inflammatory diseases, including RA. In addition to its kinase activity, IRAK4 has a kinase-independent scaffolding function, which is essential for formation of the Myddosome oligomeric complex and subsequent production of proinflammatory cytokines.
The function of IRAK4 is only partially impacted by inhibition of kinase activity. Full suppression of IRAK4 function can only be achieved by elimination of both enzymatic and scaffolding activity. Elimination of IRAK4 kinase and scaffolding function using targeted protein degradation is expected to have broader anti-inflammatory effects compared to inhibition of kinase activity alone.
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
|---|---|---|---|---|---|---|---|---|
| Targeted Protein Degradation | ||||||||
| NX-2127 Degrader | BTK + IKZF (Oral) | B-cell malignancies |
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| NX-5948 Degrader | BTK (Oral) | B-cell malignancies |
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| NX-0479 / GS-6791 Degrader | IRAK4 (Oral) | Rheumatoid arthritis and other inflammatory diseases |
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| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Targeted Protein Elevation | ||||||||
| NX-1607 Inhibitor | CBL-B (Oral) | Immuno-oncology |
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| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Discovery Pipeline | ||||||||
| Wholly Owned | 5 targets | Undisclosed |
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| Gilead Sciences | 4 Targets | Undisclosed |
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| Sanofi | 5 Targets | Undisclosed |
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| Targeted Protein Degradation | NX-2127 DegraderBTK + IKZF (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
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| NX-5948 DegraderBTK (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
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| NX-0479 / GS-6791 DegraderIRAK4 (Oral) - Rheumatoid arthritis and other inflammatory diseases |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| Targeted Protein Elevation | NX-1607 InhibitorCBL-B (Oral) - Immuno-oncology |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| Discovery Pipeline | Wholly Owned 5 targets - Undisclosed |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| Gilead Sciences4 Targets - Undisclosed |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| Sanofi5 Targets - Undisclosed |
Preclinical IND-Enabling Phase 1a Phase 1b |
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NX-0479/GS-6791 (IRAK4 degrader)
In March 2023, Gilead Sciences exercised its option to exclusively license NX-0479, designated GS-6791, which is the first development candidate resulting from the previously announced Nurix-Gilead collaboration to discover, develop, and commercialize a pipeline of innovative targeted protein degradation therapies.
NX-0479/GS-6791 is a potent, selective, oral IRAK4 degrader that targets both the scaffold and kinase functions of the IRAK4 protein kinase to block inflammatory responses downstream of toll-like receptors (TLR) and the pro-inflammatory IL-1 cytokine family of receptors (IL-1Rs). Degradation of IRAK4 by NX-0479/GS-6791 is hypothesized to have more sustained and deeper inhibition of TLR/IL-1Rs signaling as compared to kinase inhibition due to its impact on additional signaling nodes. IRAK4 degradation has potential applications in the treatment of rheumatoid arthritis and other inflammatory diseases.
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