Nurix Therapeutics, Inc. · NASDAQ:NRIX

Nurix Therapeutics — 17th Annual Drug Discovery Chemistry 2022

31 slides from Nurix Therapeutics's conference presentation, Apr 19, 2022

1. Slide 1: Blazing a New Path in Medicine

   Nurix Therapeutics Blazing a New Path in Medicine Applying DEL Discovery to Protein Modulation 17th Annual Drug Discovery Chemistry April 19th, 2022

2. 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

3. Slide 3: Working to Create a New Category of Medicine

   Working to Create a New Category of Medicine Evolution of new therapeutic modalities Small Molecule Antibodies Nucleic Acid-Based Therapies: Adoptive Cell Nurix Protein Inhibitors Antisense, RNAi Therapy Modulation Drugs Therapeutic Gene Therapy to Increase or Proteins CRISPR DeTIL Decrease Specific

4. Slide 4: Advancing Four Wholly Owned Clinical Programs with a Deep Pipeline

   Advancing Four Wholly Owned Clinical Programs with a Deep Pipeline of Proprietary and Partnered Novel Targets Drug Program Target / Delivery Therapeutic Area Discovery IND enabling Phase 1 Phase 2 Phase 3 NX-2127 BTK + IMiD activity B-cell Malignancies Degrader Oral NX-5948 BTK B-cell Malignancies a

5. Slide 5: Nurix's DELigase Platform: Leading the Industry in Application of DEL

   Nurix’s DELigase Platform: Leading the Industry in Application of DEL for Targeted Protein Modulation • DELigaseTM is a versatile drug discovery DELigase Protein Modulation Platform platform utilizing DNA-encoded libraries (DEL) Proprietary DNA-Encoded Libraries that represent over 5 billion drug-li

6. Slide 6: NX-2127: Targeted Degrader of BTK

   NX-2127: Targeted Degrader of BTK

7. Slide 7: Nurix's BTK Degrader Portfolio: Addressing Unmet Needs for BTK-driven Malignancies

   Nurix’s BTK Degrader Portfolio: Addressing Unmet Needs for BTK-driven Malignancies • BTK inhibitors are standard of care target however mutational escape represents a major unmet need BTK Inhibitors – BTK inhibitors are approved for CLL/SLL, mantle cell lymphoma, Waldenstrom's macroglobulinemia, mar

8. Slide 8: NX-2127 Degrades Both BTK and CRBN Neosubstrate Aiolos

   NX-2127 Degrades Both BTK and CRBN Neosubstrate Aiolos BTK Degradation in TMD8 Cells Aiolos Degradation in T Cells 125 NX-2127 % Aiolos Remaining 100 %BTK Remaining Lenalidomide 100 Pomalidomide 75 75 50 50 25 25 0 0 0.001 0.01 0.1 1 10 100 1000 0.001 0.01 0.1 1 10 100 1000 10000 NX-2127 (nM) Compou

9. Slide 9: Oral Dosing of NX-2127 Degrades BTK in NHPs

   Oral Dosing of NX-2127 Degrades BTK in NHPs • Significant degradation of BTK in 4 hours and more than 90% degradation through 24 hours post dosing at the highest dose level • Once daily, oral dosing of NX-2127 maintains suppression of BTK protein levels throughout the 19-day duration of the study (N

10. Slide 10: NX-2127-001: Phase 1 First-in-Human Clinical Trial Design

    NX-2127-001: Phase 1 First-in-Human Clinical Trial Design Two-Part Phase 1 Monotherapy Trial of NX-2127 in Relapsed or Refractory B-Cell Malignancies Dose Escalation Potential Dose Expansion Objectives: - Assess safety and tolerability - Identify maximum tolerated dose CLL with BTK C481 mutation - E

11. Slide 11: Robust BTK Degradation Observed in All Patients Dosed

    Robust BTK Degradation Observed in All Patients Dosed Regardless of Baseline BTK Protein Levels BTK Levels in Circulating B Cells • Oral daily treatment of 24000 Patient 1 (CLL) 100 mg NX-2127 induced a rapid and significant 20000 Patient 2 (CLL) 200 mg decrease in BTK levels Patient 3 (MCL) 200 mg

12. Slide 12: Clinical Response Observed in First Patient

    Clinical Response Observed in First Patient Patient History: Disease at Study Entry: Safety Absolute Lymphocyte Count 60 78-year-old male Bone Marrow Involvement: 85.4% Exposure No dose interruptions or with stage IV CLL Spleen: Enlarged (15.7 cm) Cell Count (K/uL) modifications 40 Nodal Lesions: Se

13. Slide 13: L528W is Among Several Newly Identified Mutations Conferring Resistance

    L528W is Among Several Newly Identified Mutations that Confer Resistance to Noncovalent BTK Inhibitors “Our data suggest potential new therapeutic approaches to overcome the newly described BTK inhibitor resistance mechanisms. For example, these data provide a rationale for therapies aimed at addres

14. Slide 14: NX-1607: Inhibitor of CBL-B Ligase

    NX-1607: Inhibitor of CBL-B Ligase 14 ©Nurix Therapeutics. All rights reserved.

15. Slide 15: CBL-B: A Modulator of T Cell Activation and a Novel Target for Immuno-oncology

    CBL-B: A Modulator of T Cell Activation and a Novel Target for Immuno-oncology • CBL-B is an E3 ligase that regulates the immune system by specifically ubiquitinating proteins involved in signaling through the T cell antigen receptor • Blocking CBL-B removes a brake on the immune system APC CBL-B in

16. Slide 16: NX-1607 Enhances IL-2 and IFN-γ Secretion in TCR Stimulated Primary Human T cells

    Optimized CBL-B Inhibitor NX-1607 Enhances IL-2 and IFN-γ Secretion in TCR Stimulated Primary Human T cells IL-2 anti-CD3/CD28 IL-2 anti-CD3 1000 Cytokine response 60000 Baseline response 750 APC IL-2 pg/mL IL-2 pg/mL 40000 500 MHC CD80/86 20000 250 Signal 1 Signal 2 TCR CD28 2400 pg/mL 20 pg/mL 0 0

17. 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 Vehicle NX-1607 Anti-PD-1 NX-1607 + Anti-PD-1 Colorectal (CT26) Colorectal (MC38) Triple-negative breast (4T1) NX-1607 antitumor Tumor Volume Tumor Volume Tumor Volume efficacy is abrogated 12

18. Slide 18: 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 Potential Dose Expansion Objectives: Melanoma • Assess safety and tolerability Dose • Identify maximum tolerated dose Level 6 Squamous Cell Carcino

19. Slide 19: Expanding our Discovery Pipeline using DELigase

    Expanding our Discovery Pipeline using DELigase

20. Slide 20: How We're Implementing DEL for Protein Modulation

    How We’re Implementing DEL for Protein Modulation • Proprietary DEL scaffold libraries are unique to Nurix; custom scaffold DELs are distinct in the field and afford more chemical novelty vs other collections • Extensive in-house protein chemistry and affinity selection expertise to tackle difficult

21. Slide 21: Integrated Platform Enabling Novel Drug Discovery

    Integrated Platform Enabling Novel Drug Discovery Binders can span the Parallel screening DNA attachment can surface of the protein enables identification be used to guide of selective binders or degrader linker DEL linker- inhibitors placement attachment Kinase A Selective Kinase B Selective Litera

22. Slide 22: Multiple Chemical Series Identified Through Different Screening Approaches

    Multiple Chemical Series Identified Through Different Screening Approaches E2~Ub Binding Assay N-Avi Ub HTS DEL Fragment Biochemical TKB Lib size 300K 1X109 1600 Screening RING P # of 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

23. Slide 23: Over 30 Binding Conditions Applied to Interrogate CBL

    Over 30 Binding Conditions Applied to Interrogate CBL CBL-B Apo CBL-B + binders C-CBL Apo C-CBL + binders TKB TKB TKB TKB LHR LHR LHR LHR Identify novel chemical matter for CBL-B while Differentiate CBL-B versus C-CBL binders differentiating known versus novel binding pockets 23 ©Nurix Therapeutics.

24. Slide 24: Selective Binder for CBL-B Identified

    Selective Binder for CBL-B Identified DEL Screen Affinity Plot Biophysical assessment of NRX-48: BB2 Open State Closed State CBL-B SPR NRX-48 KD 5 µM ClogP = 3.7 Ksol = 20 uM C-CBL SPR KD >200 µM BB1 BB3 24 ©Nurix Therapeutics. All rights reserved.

25. Slide 25: DEL Screening Delivered Differentiated Chemical Matter, Unlocking Challenging Protein Target

    DEL Screening Delivered Differentiated Chemical Matter, Unlocking Challenging Protein Target DEL-derived degrader series: CBL-B C-CBL DC50 (uM) 0.9 - Dmax (%) 72 19 DEL-derived inhibitor series CBL HiBit Assay NRX-94 100 HTS-derived inhibitor series % Protein Remaining 80 60 40 DEL enabled the ident

26. Slide 26: Potent SARS Binder Directly from DELigase Platform

    Potent SARS Binder Directly from DELigase Platform Nurix DELs consist of billions of DNA-barcoded compounds chemotype 1 BB2 chemotype 2 chemotype 3 chemotype 4 BB2 Chemotype 3 (blue) BB3 BB1 SARs COV-2 BB3 BB1 Protein Target (gray) 1. Screen Nurix DEL collection 2. Identify rare small molecule 3. So

27. Slide 27: Potent, Reversible Mpro Inhibitor Identified using DEL

    Potent, Reversible Mpro Inhibitor Identified using DEL NRX-1 X-ray of NRX-1 bound to Mpro KD 0.95 nM Mpro KD = 1.1 nM (n=3) Mpro IC50 = 2.0 nM 1.6Å MW <540 LE = 0.31 Solubility = 245 µM 100 % Mpro activity IC50 2.0 nM 50 0 Cys145 10 -4 10 -3 10 -2 [cpd], μM • The initial DEL hit is the most potent,

28. Slide 28: Nurix Mpro Inhibitors Demonstrate in vitro Antiviral Activity

    Nurix Mpro Inhibitors Demonstrate in vitro Antiviral Activity Comparable to Approved Agent Compounds screened in a 2-day in vitro antiviral assay using SARS-CoV-2/WA1 in Calu-3 cells 150 NRX-2 % infected cells, NRX-4 rel. to vehicle 100 NRX-3 Mpro IC50 (µM) PF-07321332 PF-07321322 50 PF-07321332 NRX

29. Slide 29: NRX-4 Compares Favorably to Nirmatrelvir Across a Range of Parameters

    NRX-4 Compares Favorably to Nirmatrelvir Across a Range of Parameters NRX-4 PF-07321332, nirmatrelvir Chemical starting point Custom scaffold DEL Peptide substrate Chiral centers 1 6 Mechanism Non-covalent Reversible-covalent Approved for emergency Clinical Status Pre-clinical use, co-dosed with Rit

30. Slide 30: Advancing Our Pipeline to Multiple Clinical Milestones in 2022

    Advancing Our Pipeline to Multiple Clinical Milestones in 2022 NX-2127 NX-1607 • Initiate Phase 1b trial in mid-2022 • Establish Phase 1a PK/PD in mid-2022 • Present additional Phase 1a clinical results in H2 2022 DeTIL-0255  Dose first patient in Phase 1 trial in H1 2022 NX-5948 • Phase clinical u

31. Slide 31: Thank you

    Thank you Nurix Therapeutics

Nurix Therapeutics — 17th Annual Drug Discovery Chemistry 2022 on 6ix