| 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 |
| |||||
| NX-5948 Degrader | BTK (Oral) | B-cell malignancies |
| |||||
| NX-0479 / GS-6791 Degrader | IRAK4 (Oral) | Rheumatoid arthritis and other inflammatory diseases |
 | |||||
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Targeted Protein Elevation | ||||||||
| NX-1607 Inhibitor | CBL-B (Oral) | Immuno-oncology |
| |||||
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Discovery Pipeline | ||||||||
| Wholly Owned | 5 targets | Undisclosed |
| |||||
| Gilead Sciences | 4 Targets | Undisclosed |
| |||||
| Sanofi | 5 Targets | Undisclosed |
| |||||
| Targeted Protein Degradation | NX-2127 DegraderBTK + IKZF (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| NX-5948 DegraderBTK (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| 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 |
|
Eliminating a Bad Actor in Cancer: Nurix’s Targeted Cancer Therapy Programs
BTK Degraders
The U.S. Food and Drug Administration and global regulatory agencies have approved several inhibitors of Bruton’s tyrosine kinase (BTK), which are now the standard of care across multiple tumor types. We believe that removal of the BTK protein through Targeted Protein Degradation could generate superior outcomes for patients who no longer respond to or do not tolerate current therapies, including patients whose tumors have acquired resistance to current therapies through mutations in the BTK protein.
BTK is a validated clinical target for the treatment of hematologic malignancies and autoimmune diseases. BTK is a master regulator of B-cell activity, and inhibition of BTK results in improved clinical outcomes for patients with a variety of B-cell mediated cancers such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).
We have developed two unique and functionally distinct BTK degraders that harness cereblon (CRBN), an E3 ligase active in hematopoietic cells. Cereblon itself is the target for a class of drugs with immunomodulatory activity, including lenalidomide and pomalidomide that induce cereblon to degrade so-called neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). We have designed two BTK degraders with and without the ability to induce neosubstrate degradation, creating two functionally distinct drug candidates to address the unmet medical needs across indications and lines of therapy.
| 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 |
| |||||
| NX-5948 Degrader | BTK (Oral) | B-cell malignancies |
| |||||
| NX-0479 / GS-6791 Degrader | IRAK4 (Oral) | Rheumatoid arthritis and other inflammatory diseases |
| |||||
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Targeted Protein Elevation | ||||||||
| NX-1607 Inhibitor | CBL-B (Oral) | Immuno-oncology |
| |||||
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Discovery Pipeline | ||||||||
| Wholly Owned | 5 targets | Undisclosed |
| |||||
| Gilead Sciences | 4 Targets | Undisclosed |
| |||||
| Sanofi | 5 Targets | Undisclosed |
| |||||
| Targeted Protein Degradation | NX-2127 DegraderBTK + IKZF (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| NX-5948 DegraderBTK (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| 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 |
|
NX-2127 (BTK + IKZF degrader for B-cell malignancies)
NX-2127 is an oral small molecule that combines the activity of a targeted BTK degrader with cereblon immunomodulatory activity of an IKZF degrader. Cereblon immunomodulatory drugs that induce degradation IKZF1 and IKZF3 such as lenalidomide and pomalidomide are FDA approved for a variety of hematologic malignancies including multiple myeloma, follicular lymphoma, and mantle cell lymphoma. We hypothesize that the combination of BTK degradation and cereblon immunomodulatory activity will have enhanced therapeutic benefit in patients suffering from a variety of B-cell malignancies.
Initial clinical data support the activity of NX-2127 in patients whose tumors harbor either wild-type BTK or BTK with mutations conferring clinical resistance to FDA approved agents. Initial clinical data also confirm potent BTK degradation with once daily oral dosing. NX-2127 is being tested in an ongoing Phase 1 trial for patients with B-cell malignancies who have failed prior treatments.
NX-5948 (BTK degrader for B-cell malignancies)
NX-5948 is an oral small molecule degrader of BTK. Preclinical data support the activity of NX-5948 in tumor models harboring either wild-type BTK or BTK with mutations conferring clinical resistance to leading FDA approved agents. NX-5948 lacks cereblon immunomodulatory activity, differentiating it from NX-2127, and has demonstrated the ability to cross the blood brain barrier in animal models. NX-5948 has also demonstrated activity in animal models of autoimmune disease.
NX-5948 is being tested in an ongoing Phase 1 trial for patients with B-cell malignancies who have failed prior treatments.
Building Immunity to Cancer: Nurix’s Immuno-Oncology Program
Targeted Protein Elevation: CBL-B Inhibition
Casitas B-lineage lymphoma proto-oncogene-b (CBL-B) is an E3 ligase that is expressed in immune cells and in the context of cancer, acts as a brake on the immune system. CBL-B functions as an intracellular checkpoint that negatively regulates T cell activation, NK cell activity, and immune response through degradation of specific proteins.
Conversely, inhibition of CBL-B with a small molecule drug activates T cells, a goal in the treatment of cancer, where T cells and the entire immune system can be mobilized to destroy a tumor. Nurix has developed two CBL-B inhibitors, NX-1607 for oral administration and NX-0255 for ex vivo use in combination with adoptive cell therapies such as tumor infiltrating lymphocytes (TIL) or chimeric antigen receptor T cells (CAR T).
| 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 |
| |||||
| NX-5948 Degrader | BTK (Oral) | B-cell malignancies |
| |||||
| NX-0479 / GS-6791 Degrader | IRAK4 (Oral) | Rheumatoid arthritis and other inflammatory diseases |
| |||||
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Targeted Protein Elevation | ||||||||
| NX-1607 Inhibitor | CBL-B (Oral) | Immuno-oncology |
| |||||
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Discovery Pipeline | ||||||||
| Wholly Owned | 5 targets | Undisclosed |
| |||||
| Gilead Sciences | 4 Targets | Undisclosed |
| |||||
| Sanofi | 5 Targets | Undisclosed |
| |||||
| Targeted Protein Degradation | NX-2127 DegraderBTK + IKZF (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| NX-5948 DegraderBTK (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| 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 |
|
NX-1607 (oral CBL-B inhibitor for solid tumors)
NX-1607 is an oral, small molecule CBL-B inhibitor. In multiple preclinical animal models of both colorectal cancer and triple negative breast cancer, NX-1607 demonstrates anti-tumor activity and prolongs survival. The combination of NX-1607 with an anti-PD-1 antibody provides additional benefit in animal models. The anti-tumor activity of NX-1607 is dependent on both CD8+ T cells and NK cells.
We are planning to develop NX-1607 in multiple solid tumors and lymphoma as monotherapy or in combination with other complementary therapies such as anti-PD-1 antibodies. NX-1607 may also have utility in combination with cell therapies such as TIL or CAR T. A Phase 1 clinical trial of NX-1607 as a single agent therapy in multiple oncology indications is ongoing.
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 |
| |||||
| NX-5948 Degrader | BTK (Oral) | B-cell malignancies |
| |||||
| NX-0479 / GS-6791 Degrader | IRAK4 (Oral) | Rheumatoid arthritis and other inflammatory diseases |
| |||||
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Targeted Protein Elevation | ||||||||
| NX-1607 Inhibitor | CBL-B (Oral) | Immuno-oncology |
| |||||
| Drug Program | Target/Delivery | Therapeutic Area | Discovery | IND enabling | Phase 1a | Phase 1b | ||
| Discovery Pipeline | ||||||||
| Wholly Owned | 5 targets | Undisclosed |
| |||||
| Gilead Sciences | 4 Targets | Undisclosed |
| |||||
| Sanofi | 5 Targets | Undisclosed |
| |||||
| Targeted Protein Degradation | NX-2127 DegraderBTK + IKZF (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| NX-5948 DegraderBTK (Oral) - B-cell malignancies |
Preclinical IND-Enabling Phase 1a Phase 1b |
|
| 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 |
|
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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