Immunomodulatory agents' mechanism helped the understanding of multiple myeloma come a long way1,2
Research is exploring maximizing mechanistic performance through CELMoD1,3
CELMOD=cereblon E3 ligase modulation
Immunomodulatory agents’ ability to kill cancer cells and stimulate the immune system is limited by the potential of their mechanism1,3-7*†
Research continues into CELMoD to harness the potential of this mechanism in multiple myeloma1
*Based on in vitro studies examining the mechanism of immunomodulatory agents as well as studies using human multiple myeloma cell lines that investigated the effects of immunomodulatory agents on multiple myeloma cell killing and the immune system3-7
†Current immunomodulatory agents have an ~20% rate of inducing the closed/active state of cereblon based on in vitro data1,3,8,9
Deeper understanding of immunomodulatory agents’ mechanism shows that they activate cereblon, a protein found within cells as part of the E3 ubiquitin-ligase complex. Its main role is to tag specific proteins for breakdown, known as degradation1,10
Cereblon in the active state works in 2 ways1,4-7,11‡§
‡The active state occurs when cereblon transitions to a closed conformation1
§Based on in vitro data from studies using human multiple myeloma cell lines that investigated the effects of immunomodulatory agents on protein degradation, multiple myeloma cell killing, and the immune system4-7,11
Immunomodulatory agents’ potential to
create an active state of cereblon is
limited by their inefficient binding only
within a specific pocket of cereblon1,12†
Immunomodulatory agents’ binding
is limited to the tri-TRP pocket3,13
†Current immunomodulatory agents have an ~20% rate of inducing
the closed/active state of cereblon based on in vitro data1,3,8,9
CELMoD (cereblon E3 ligase modulation) is being researched to potentially find ways to:
- Maximize cereblon in the active state1
- Create faster and deeper protein degradation1,14
- Enhance killing of cancer cells and immune stimulation, including reversal of T-cell exhaustion1
Under exploration is a purposefully designed mechanism that may have the power to unlock new potential of cereblon modulation1,3
Frequently Asked Questions
tri-TRP pocket=tri-tryptophan pocket
References: 1. Liu Y, Mo CC, Hartley-Brown MA, et al. Expert Rev Hematol. 2024;17(8):445-465. doi:10.1080/17474086.2024.2382897 2. Costacurta M, He J, Thompson PE, Shortt J. J Pers Med. 2021;11(11):1185. doi:10.3390/jpm11111185 3. Watson ER, Novick S, Matyskiela ME, et al. Science. 2022;378(6619):549-553. doi:10.1126/science.add7574 4. Davies FE, Raje N, Hideshima T, et al. Blood. 2001;98(1):210-216. doi:10.1182/blood.v98.1.210 5. Hideshima T, Chauhan D, Shima Y, et al. Blood. 2000;96(9):2943-2950. 6. Görgün G, Calabrese E, Soydan E, et al. Blood. 2010;116(17):3227-3237. doi:10.1182/blood-2010-04-279893 7. Hayashi T, Hideshima T, Akiyama M, et al. Br J Haematol. 2005;128(2):192-203. doi:10.1111/j.1365-2141.2004.05286.x 8. Mo Z, Groocock L, Wood S, et al. Blood Cancer Discov. 2026;7(1):104-128. doi:10.1158/2643-3230.BCD-25-0059 9. Mo Z, Groocock L, Wood S, et al. Supplementary information. Blood Cancer Discov. 2026;7(1):104-128. doi:10.1158/2643-3230.BCD-25-0059 10. Shi Q, Chen L. J Immunol Res. 2017;2017:9130608. doi:10.1155/2017/9130608 11. Krönke J, Udeshi ND, Narla A, et al. Science. 2014;343(6168):301-305. doi:10.1126/science.1244851 12. Thakurta A, Pierceall WE, Amatangelo MD, Flynt E, Agarwal A. Oncotarget. 2021;12(15):1555-1563. 13. Matyskiela ME, Zhang W, Man HW, et al. J Med Chem. 2018;61(2):535-542. doi:10.1021/acs.jmedchem.6b01921 14. Bjorkland CC, Kang J, Amatangelo M, et al. Leukemia. 2020;34(4):1197-1201. doi:10.1038/s41375-019-0620-8 15. Klaips CL, Jayaraj GG, Hartl FU. J Cell Bio. 2018;217(1):51-63. doi:10.1083/jcb.201709072 16. Al-Jarrad A, Alouch SS, Chawla Y, Gonsalves WI. Blood Lymphat Cancer. 2025;15:1-10. doi:10.2147/BLCTT.S492116 17. Kim J, Kim SJ. Cancer Res Treat. 2025;57(4):905-922. doi:10.4143/crt.2025.440
