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Strategies We Are Pursuing

Targeting the Ubiquitin Proteasome System

Overall Targeted Protein Degradation Landscape

E1 Inhibitors
E2 Inhibitors
E3 Inhibitors
E3 Modulators
Proteasome Inhibitors
DUB Inhibitors
Cereblon-based Modulators
VHL-based Modulators
IAP-based Modulators
Other E3 Ligase Modulators
Ligase
Modulators
Ligand-Directed Degraders

DUB, deubiquitinase; IAP, inhibitor of apoptosis; TP, target protein; VHL, von Hippel-Lindau.

Both strategies degrade proteins that contribute to disease progression.1-6 The exact effect of each cereblon E3 ligase
modulator or ligand-directed degrader differs depending on the target proteins that are degraded, and can include
antitumor effects, immunomodulatory effects, therapeutic effects, and/or antiangiogenic benefits.1-8

Cereblon E3 ligase modulators1-4,9,10:

  • Act as molecular glue to alter the target
    protein–binding properties of cereblon E3
    ligase to promote interaction with proteins
    of therapeutic interest

    • The ligase modulators bind to the surface of an E3 ligase

    • Modulator binding to the E3 ligase modifies the
      binding surface and confers differentiated
      substrate specificity to the co-opted E3 ligase

    • This results in degradation of target proteins that
      can interact with the modulator-bound E3 ligase

    Learn More
Ligand-directed degraders6:

  • Engineered with 2 domains connected via
    a linker designed to interact with both:

    • The E3 ligase

    • The target protein

    Learn More

We Are Committed to Bringing Innovation
to Our Patients and Have Over 25 Years of
Targeted Protein Degradation Experience

Our Leadership Over Time

The first company to launch multiple successful targeted protein degrader agents (immunomodulators, a subgroup of cereblon E3 ligase modulators)11

Ongoing research to expand the science of protein homeostasis and understand its therapeutic potential

Supported by BMS

Supported by BMS and other parties

Supported by other parties

1980s

Ubiquitin proteasome pathway is characterized, its role in protein degradation identified by the Hershko, Ciechanover, Heller, and Rechnsteiner groups12-16

1990s

Immunomodulators in development at BMS17

2000s

FDA approves first BMS-developed immunomodulator18

2010s

A BMS-developed immunomodulator becomes
standard of care in multiple myeloma19

FDA approves second BMS-developed
immunomodulator20

Cereblon E3 ligase modulator program

Cereblon is identified as a mediator of targeted protein
degradation by BMS5,9

Ikaros (IKZF) and Aiolos are identified by BMS and the Ebert group as 2 key targets of immunomodulator-mediated protein degradation1,3

The downstream effects of IKZF degradation are characterized by the Kaelin group2

BMS development of an additional cereblon E3 ligase modulator is initiated in multiple disease areas: lymphoma, multiple myeloma, acute myeloid leukemia, and lupus21-23

2020+

Trials by BMS assessing new cereblon E3 ligase modulators targeting GSPT1 and IKZF/Aiolos are ongoing in lymphoma, multiple myeloma and acute myeloid leukemia24-32

A BMS trial investigating a ligand-directed degrader in prostate cancer is ongoing33,34

Targeted Protein Degradation
and Drug
Development at BMS

Video

The Future of Targeted
Protein Degradation

We continue to develop cereblon E3 ligase modulators and
ligand-directed degraders that may be able to address previously
“undruggable” proteins that play a role in disease pathology.

We are working on agents with a mechanism of action similar
to cereblon E3 ligase modulators, but which co-opt E3 ligase
complex members other than cereblon.

Our ongoing investments further our commitment and
leadership in providing solutions that may selectively degrade
previously “undruggable” protein targets with clinical relevance.

References

  1. Krönke J et al. Science. 2014;343(6168):301-305.

  2. Lu G et al. Science. 2014;343(6168):305-309.

  3. Gandhi AK et al. Br J Haematol. 2014;164(6):811-821.

  4. Ito T, Handa H. Int J Hematol. 2016;104(3):293-299.

  5. Matyskiela ME et al. Nature. 2016;535(7611):252-257.

  6. BMS. Data on file.

  7. Nowakowski GS. Blood. 2015;126(6):698-700.

  8. Ito T et al. Science. 2010;327(5971):1345-1350.

  9. Chamberlain PP et al. Nat Struct Mol Biol. 2014;21(9):803-809.

  10. Hagner PR et al. Blood. 2015;126(6):779-789.

  11. Chamberlain PP, Hamann LG. Nat Chem Biol. 2019;15(10):937-944.

  12. Hershko A. J Biol Chem. 1988;263(30):152​37​-1​52​4​0.

  13. Hershko A et al. J Biol Chem. 1983;258(13):82​06​-8​21​4.

  14. Hershko A et al. Proc Natl Acad U S A. 1984;81:16​19-​16​23.

  15. Hough R et al. J Biol Chem. 1986;261(5):240​0​-​24​08.

  16. Hough R et al. J Biol Chem. 1987;262(17):83​03​-83​13.

  17. Holstein SA et al. Ther Adv Hematol. 2018;9(7);175-190.

  18. U.S. Food and Drug Administration. Lenalidomide (Revlimid).
    https://www.fda.gov/drugs/resources-information-approved-drugs/lenalidomide-revlimid. Accessed January 22, 2021.

  19. Anderson KC et al. J Natl Compr Canc Netw. 2009;7(9):908-942.

  20. U.S. Food and Drug Administration. Pomalyst.
    https://www.accessdata.fda.gov/scripts/cder/daf/
    index.cfm?
    event=overview.process&ApplNo=204026. Accessed January 22, 2021.

  21. A Pilot Study of CC-220 to Treat Systemic Lupus Erythematosus.
    NCT02185040. https://clinicaltrials.gov/ct2/show/NCT02185040.
    Accessed January 22, 2021.

  22. A Study to Determine Dose, Safety, Tolerability and Efficacy of CC-220 Monotherapy, and in Combination With Other Treatments in Subjects With Multiple Myeloma. NCT02773030.
    https://clinicaltrials.gov/ct2/show/NCT02773030.
    Accessed January 22, 2021.

  23. A Safety and Efficacy Trial of JCAR017 Combinations in Subjects With Relapsed/Refractory B-cell Malignancies (PLATFORM). NCT03310619. https://clinicaltrials.gov/ct2/show/NCT03310619.
    Accessed January 22, 2021.

  1. A Dose Finding and Safety Study of CC-220, Alone and in Combination With an Anti-CD20 Monoclonal Antibody (mAb) in Subjects With Relapsed or Refractory Lymphomas. NCT04464798. https://clinicaltrials.gov/ct2/show/NCT04464798. Accessed January 22, 2021.

  2. Surka C et al. Blood. 2021;137(5):661-677.

  3. Iberdomide (CC-220) Maintenance After ASCT in Newly Diagnosed MM Patients. NCT04564703. https://clinicaltrials.gov/ct2/show/NCT04564703. Accessed January 22, 2021.

  4. Iberdomide Combined With Low-dose Cyclophosphamide and Dexamethasone (ICON). NCT04392037. https://clinicaltrials.gov/ct2/show/NCT04392037.
    Accessed January 22, 2021.

  5. A Safety, PK and Efficacy Study of CC-92480 Monotherapy and in Combination With Dexamethasone in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM). NCT03374085. https://clinicaltrials.gov/ct2/show/NCT03374085.
    Accessed April 7, 2021.

  6. A Study to Determine the Recommended Dose and Regimen and Evaluate the Safety and Preliminary Efficacy of CC-92480 in Combination With Standard Treatments in Subjects With Relapsed or Refractory Multiple Myeloma (RRMM) and Newly Diagnosed Multiple Myeloma (NDMM). NCT03989414. https://clinicaltrials.gov/ct2/show/NCT03989414.
    Accessed April 7, 2021.

  7. Lopez-Girona A et al. Blood. 2019;134(S1):1812.

  8. A Safety and Preliminary Efficacy Study of CC-99282 in Combination With Obinutuzumab in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. NCT04434196.
    https://clinicaltrials.gov/ct2/
    show/NCT04434196. Accessed April 8, 2021

  9. A Safety and Preliminary Efficacy Study of CC-99282, Alone and in Combination With Rituximab in Subjects With Relapsed or Refractory Non-Hodgkin Lymphomas (R/R NHL). NCT03930953. https://clinicaltrials.gov/ct2/show/NCT03930953.
    Accessed April 8, 2021.

  10. BMS Investor Series. Early Pipeline & Immuno-oncology. June 22, 2020.
    https://s21.q4cdn.com/104148044/files/
    doc_presentations/2020/BMY-Investor
    -Series-Day1.pdf. Accessed April 7, 2021.

  11. Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CC-94676 in Subjects With Metastatic Castration-Resistant Prostate Cancer. NCT04428788. https://clinicaltrials.gov/ct2/
    show/NCT04428788.
    Accessed April 7, 2021.