Nurix Therapeutics, Inc. · NASDAQ:NRIX
Nurix Therapeutics — 3rd Annual Ligase Targeting Drug Development (April 2023)
28 slides from Nurix Therapeutics's conference presentation, Apr 12, 2023
Slide 1: Exploring Success with Targeting a Novel E3 Ligase with a Small Molecule Inhibitor
Leader in Targeted Protein Modulation Exploring Success with Targeting a Novel E3 Ligase with a Small Molecule Inhibitor NX-1607: A first-in-class CBL-B inhibitor in the clinic Gwenn M Hansen, Ph.D. 3rd Annual Ligase Targeting Drug Development Boston, MA April 12, 2023
Slide 2: Important Notice and Disclaimers
Important Notice and Disclaimers This presentation contains statements that relate to future events and expectations and as such constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. When or if used in this presentation, the words “anticipa
Slide 3: Nurix Drugs Engage Ligases for the Treatment of Cancer
Nurix Drugs Engage Ligases for the Treatment of Cancer Targeted Protein Modulation: TPM = TPD + TPE A Powerful Targeted Protein Cellular System Elevation (TPE) Harness ligases to decrease specific protein levels Inhibit ligases to increase specific protein levels Targeted Protein Ubiquitin is ligate
Slide 4: Nurix is Advancing a Pipeline of Proprietary and Partnered Programs
Nurix is Advancing a Pipeline of Propriety and Partnered Programs in Oncology and Inflammatory Diseases MOA Drug program Target/delivery Therapeutic area Discovery IND enabling Phase 1a Phase 1b NX-2127 BTK-IKZF B-cell malignancies Degrader Oral NX-5948 BTK TPD B-cell malignancies Degrader Oral NX-0
Slide 5: Targeting CBL-B Enhances Antitumor Response
Targeting CBL-B Enhances Antitumor Response A Master Orchestrator of the Immune System CBL-B mediated mechanisms strongly restrains a productive anti-tumor response Lymph node T cell CBL-B Blood CBL-B inhibition increases: • DC and NK infiltration and function Dying Tumor Tumor DC • T cell priming t
Slide 6: CBL-B is a Master Orchestrator of Immune Cell Activation
CBL-B is a Master Orchestrator of Immune Cell Activation Loss of CBL-B ligase activity results in hyperactive T cells that can reject tumors IL-2 secretion in KO and ligase inactive T cells ex vivo Ligase-inactive cbl-b knock-in mice inhibit tumor growth (TC-1 syngeneic model). Het Inactive ligase m
Slide 7: Targeted Protein Elevation
Targeted Protein Elevation E3 Ligase Inhibition Raises Substrate Levels Native State: Normal Levels of Target Ligase Inhibition: Increased Target Abundance NRX – E3 inhibitor Ub Target proteins Target proteins Ub E2 E2 E3 ligase E3 ligase Proteasome Proteasome E3 ligase maintains proper E3 Ligase In
Slide 8: Multiple Screening Methodologies Yielded Chemical Matter for CBL-B
Multiple Screening Methodologies Yielded Chemical Matter for CBL-B E2~Ub Binding Assay N-Avi Ub HTS DEL Fragment Biochemical TKB Lib size 300K 1X109 1600 CBL-B Screening # of RING P 1 2 1 Series RING Hit TKB 28 uM 2.4 uM 1800 uM Affinity Hit mwt 338 537 211 Hit LE 0.27 0.22 0.33 Affinity Screening M
Slide 9: Crystal Structure Confirms Binding Mode as Intramolecular Glue
Crystal Structure Confirms Binding Mode as Intramolecular Glue 2.0 Å Nurix CBL-B inhibitors bind to closed-state conformation of E3 ligase and prevents phosphorylation 9
Slide 10: Over 10,000-fold Enzymatic Potency Improvement Achieved
Over 10,000-fold Enzymatic Potency Improvement Achieved While Improving Molecular Properties 2017 HTS hit HTS hit, single enantiomer 2018 2019 Enzymatic potency (uM) ~ 10,000x potency improvement Clinical candidate range LipE 10
Slide 11: NX-1607 Mechanism of Action: Intramolecular Glue
NX-1607 Mechanism of Action: Intramolecular Glue CBL-B is in Equilibrium Between Closed and Opened State E2 Y363 Y363 RING TKB TKB Closed State Opened State INACTIVE 11
Slide 12: NX-1607 Mechanism of Action: Intramolecular Glue
NX-1607 Mechanism of Action: Intramolecular Glue Substrate protein E2 E2 Y363 p Y363 pY363 RING 1. Kinase TKB TKB 2. E2/substrate TKB Closed State Opened State Phosphorylation locks INACTIVE CBL-B in the ACTIVE Conformation Immune Response 12
Slide 13: NX-1607 Mechanism of Action: Intramolecular Glue
NX-1607 Mechanism of Action: Intramolecular Glue Substrate protein E2 E2 NX-1607 Y363 p Y363 pY363 RING RING 1. Kinase TKB TKB TKB 2. E2/substrate TKB NX-1607 acts as an Closed State Opened State Phosphorylation locks intramolecular glue INACTIVE CBL-B in the ACTIVE forcing CBL-B in its Conformation
Slide 14: NX-1607 Increases IL-2 and IFN-γ Secretion in Primary Human T cells
NX-1607 Increases IL-2 and IFN-𝛄𝛄 Secretion in TCR Stimulated Primary Human T cells IL-2 Anti-CD3 IL-2 Anti-CD3/CD28 NX-1607 increases TCR stimulation-dependent production of IL-2 and IFN-𝛄𝛄 in primary human T cells IFN-𝛄𝛄 Anti-CD3 IFN-𝛄𝛄 Anti-CD3/CD28 NX-1607 has no impact in the absence…
Slide 15: NX-1607 Increases Secretion of Pro-Inflammatory Cytokines in Human NK cells
NX-1607 Increases Secretion of Pro-Inflammatory Cytokines in Human NK cells IFN-𝛄𝛄 TNF-⍺ NX-1607 increases stimulation-dependent production of IFN-𝛄𝛄 and TNF-⍺ in primary human NK cells NX-1607 has no impact in the Baseline Response absence of NK cell stimulation, as measured by cytokine NK…
Slide 16: Single-Agent NX-1607 Induces Antitumor Response in Multiple Models
Single-Agent NX-1607 Induces Antitumor Response in Multiple Models NX-1607 NX-1607 NX-1607 Reduced Tumor Volume Prolonged Survival Reduced Tumor Volume Colorectal Triple-Negative Breast B Cell Lymphoma 100 Vehicle 1400 Vehicle Tumor Volume (mm3) NX-1607 1200 NX-1607 75 1000 % Survival p=<0.0001 800
Slide 17: NX-1607 and Anti-PD-1 Synergize to Enhance Anti-tumor Effects
NX-1607 and Anti-PD-1 Synergize to Enhance Anti-tumor Effects and Survival of Mice in Multiple Tumor Models Colorectal (CT26) Colorectal (MC38) Triple-Negative Breast (4T1) Day 28 4T1 Lung Metastases p<0.01 15000 # Metastatic Colonies p<0.01 10000 5000 200 100 0 Vehicle NX-1607 anti-PD-1 NX-1607+ant
Slide 18: NX-1607 Induces Dose Dependent T and NK Cell Intratumoral Infiltration
NX-1607 Treatment Induces Dose Dependent T and NK Cell Intratumoral Infiltration and Enhanced Function Abundance Vehicle NX-1607 10 mg/kg NX-1607 30 mg/kg * p<0.05; ** p < 0.01; *** p < 0.001 Function Tumor-bearing mice treated for 18 days with NX-1607 at 10 or 30 mg/kg. Tumor microenvironment profi
Slide 19: Combination of NX-1607 and Rituximab Enhances Anti-tumor Activity
Combination of NX-1607 and Rituximab Enhances Anti-tumor Activity in a Human NHL Animal Model NX-1607 Strongly Potentiate Rituximab-Directed NK Cell ADCC Against Tumor Cells NX-1607-mediated NK activation NK depletion abrogates NX-1607 and potentiates rituximab antitumor activity NX-1607 + Rituximab
Slide 20: UbiScan Identified Direct CBL Substrates Within the TCR Signaling Cascade
UbiScan Identified Direct CBL Substrates Within the T Cell Receptor (TCR) Signaling Cascade Decreased signal represents direct substrates ubiquitinated by CBL-B ligase activity Inhibiting CBL-B decreases ubiquitination of important T Cell receptor signaling molecules 20
Slide 21: Phospho-Protein Flow Cytometry Assay Identified Proximal Biomarkers
Phospho-Protein Flow Cytometry Assay Identified Proximal Biomarkers • Human PBMCs were stimulated with or without CBL-B inhibition Phosphorylation of proximal biomarkers in CD8+ T cells • Expression levels were determined for phospho- proteins downstream the TCR signaling • Overlapping results from
Slide 22: Dose Dependent Increases of CBL-B Proximal Biomarker Correlates with Antitumor Effects
Dose Dependent Increases of CBL-B Proximal Biomarker Correlates with Antitumor Effects of NX-1607 Pharmacodynamic relationship in mice following NX-1607 dosing 100 %Phosho pHS1+/CD8+ 80 mouse T Cells 60 Efficacious 40 Range 20 0 0.1 1 10 100 NX-1607 (mg/kg) In vivo efficacy observed between 10-60 mp
Slide 23: NX-1607-101: Phase 1 first-in-human clinical trial design
NX-1607-101: Phase 1 first-in-human clinical trial design Two-Part Phase 1 Monotherapy Trial of NX-1607 in Relapsed or Refractory Tumors Dose Escalation Cohort Expansion Objectives: Immune Checkpoint-Resistant • Assess safety and tolerability Tumors • Identify maximum tolerated dose • Evaluate PK/PD
Slide 24: NX-1607-101 Interim PK Results Suggest Linear PK
NX-1607-101 Interim PK Results Suggest Linear PK • Preliminary PK data suggest NX-1607 has dose-proportional exposures and a mean half-life of 6 to 8 hours at doses ranging from 5 to 50 mg Cycle 1 Day 1 Dose Cmax AUC0-last Tmax t1/2 (ng/mL) (h*ng/mL) (h) (h) 5 mg 4.35 26.2 2.0 7.72 (n=1) 15 mg 16.2
Slide 25: Characterization of a Novel Biomarker and First Evidence of Target Engagement
Characterization of a Novel Biomarker and First Evidence of Target Engagement for a CBL-B Inhibitor in the Clinic Human whole blood and dose projection modeling Clinical data Maximal % pHS1+ expressing CD8+ T cells observed in C1D1 25
Slide 26: NX-1607-101 Clinical Trial Status
NX-1607-101 Clinical Trial Status Dose escalation is ongoing Consistent with preclinical models, we are observing dose-dependent increases of proximal biomarkers Initial clinical data from Phase 1a is expected in H2 2023 We expect to define Phase 1b dose for cohort expansion in H2 2023 26
Slide 27: Summary and Conclusions
Summary and Conclusions E3 Ligases like CBL-B can act as gate-keepers of signaling pathways, therefore they can be powerful therapeutic targets Inhibition of E3 ligases can raise the levels of many substrate proteins in a coordinated fashion, which can be desirable in a disease setting like canc
Slide 28: Thank You!
Thank You!
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