Discovery of First-in-class PROTACs Targeting Maternal Embryonic Leucine Zipper Kinase (MELK) for the Treatment of Burkitt Lymphoma

Overview

Journal RSC Med Chem

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Jul 19

PMID 39026635

Authors

Yonghui Sun

Xiao Liu

Qiyu He

Naizhen Zhang

Wei Yan

Xucheng Lv

Yanjie Wang

Affiliations

Soon will be listed here.

Abstract

Maternal embryonic leucine zipper kinase (MELK) is a novel target for the treatment of various kinds of B-cell malignancies. However, the toxicity of inhibitors of MELK has led to clinical failures in cancer treatments. Moreover, inactivation of MELK catalytic domain is insufficient for achieving cancer cell apoptosis. To further confirm the role of MELK in Burkitt lymphoma treatment, we describe herein a structure-guided design of PROTACs targeting MELK. Through design, computer-assisted optimization and SAR studies, we developed the first-in-class MELK-targeting PROTAC MGP-39, which promoted a rapid and potent degradation of MELK in RAMOS cells. Additionally, the newly designed MELK degrader induced significant cell cycle arrest and apoptosis in cancer cells. Notably, compared to MELK inhibitors, MGP-39 has better anti-cancer activity and lower toxicity, indicating the practical role of PROTACs in avoiding the side effects of traditional inhibitors. More importantly, our results show that the use of a PROTAC can be adopted as a general and effective strategy for targeted cancer therapy.

References

Roschewski M, Staudt L, Wilson W . Burkitt's Lymphoma. N Engl J Med. 2022; 387(12):1111-1122. DOI: 10.1056/NEJMra2025746. View

Ni F, Huang X, Chen Z, Qian W, Tong X . Shikonin exerts antitumor activity in Burkitt's lymphoma by inhibiting C-MYC and PI3K/AKT/mTOR pathway and acts synergistically with doxorubicin. Sci Rep. 2018; 8(1):3317. PMC: 5820316. DOI: 10.1038/s41598-018-21570-z. View

Tomska K, Kurilov R, Lee K, Hullein J, Lukas M, Sellner L . Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma. Sci Rep. 2018; 8(1):12046. PMC: 6089937. DOI: 10.1038/s41598-018-30509-3. View

Mechali M . Replication timing and genetic instability. Science. 2022; 377(6612):1259-1260. DOI: 10.1126/science.ade4734. View

Maes A, Maes K, Vlummens P, De Raeve H, Devin J, Szablewski V . Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma. Blood Cancer J. 2019; 9(12):87. PMC: 6861269. DOI: 10.1038/s41408-019-0249-x. View

Wagener R, Seufert J, Raimondi F, Bens S, Kleinheinz K, Nagel I . The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood. 2018; 133(9):962-966. PMC: 6396176. DOI: 10.1182/blood-2018-07-864025. View

Wang L, Shao X, Zhong T, Wu Y, Xu A, Sun X . Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy. Nat Chem Biol. 2021; 17(5):567-575. DOI: 10.1038/s41589-021-00742-5. View

Sakamoto K, Kim K, Kumagai A, Mercurio F, Crews C, Deshaies R . Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A. 2001; 98(15):8554-9. PMC: 37474. DOI: 10.1073/pnas.141230798. View

Johnson C, Berdini V, Beke L, Bonnet P, Brehmer D, Coyle J . Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase. ACS Med Chem Lett. 2015; 6(1):25-30. PMC: 4291735. DOI: 10.1021/ml5001245. View

10.

Sun Y, Zhao X, Ding N, Gao H, Wu Y, Yang Y . PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 2018; 28(7):779-781. PMC: 6028582. DOI: 10.1038/s41422-018-0055-1. View

11.

Li Z, Zhou H, Zhai X, Gao L, Yang M, An B . MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function. Cell Death Dis. 2023; 14(11):733. PMC: 10638394. DOI: 10.1038/s41419-023-06264-3. View

12.

Xu W, Berning P, Erdmann T, Grau M, Bettazova N, Zapukhlyak M . mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma. Leukemia. 2022; 37(1):178-189. PMC: 9883168. DOI: 10.1038/s41375-022-01749-0. View

13.

Huang H, Seo H, Zhang T, Wang Y, Jiang B, Li Q . MELK is not necessary for the proliferation of basal-like breast cancer cells. Elife. 2017; 6. PMC: 5605198. DOI: 10.7554/eLife.26693. View

14.

Zhang Y, Zhou X, Li Y, Xu Y, Lu K, Li P . Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia. Oncogene. 2018; 37(41):5520-5533. DOI: 10.1038/s41388-018-0333-x. View

15.

Lopez C, Burkhardt B, Chan J, Leoncini L, Mbulaiteye S, Ogwang M . Burkitt lymphoma. Nat Rev Dis Primers. 2022; 8(1):78. DOI: 10.1038/s41572-022-00404-3. View

16.

Burkhardt B, Michgehl U, Rohde J, Erdmann T, Berning P, Reutter K . Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age. Nat Commun. 2022; 13(1):3881. PMC: 9259584. DOI: 10.1038/s41467-022-31355-8. View

17.

Li C, Xin P, Xiao H, Zheng Y, Huang Y, Zhu X . The dual PI3K/mTOR inhibitor NVP-BEZ235 inhibits proliferation and induces apoptosis of burkitt lymphoma cells. Cancer Cell Int. 2015; 15:65. PMC: 4486138. DOI: 10.1186/s12935-015-0213-1. View

18.

Montoya S, Bourcier J, Noviski M, Lu H, Thompson M, Chirino A . Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024; 383(6682):eadi5798. PMC: 11103405. DOI: 10.1126/science.adi5798. View

19.

Seong H, Manoharan R, Ha H . Zinc finger protein ZPR9 functions as an activator of AMPK-related serine/threonine kinase MPK38/MELK involved in ASK1/TGF-β/p53 signaling pathways. Sci Rep. 2017; 7:42502. PMC: 5307367. DOI: 10.1038/srep42502. View

20.

Toure B, Giraldes J, Smith T, Sprague E, Wang Y, Mathieu S . Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight. J Med Chem. 2016; 59(10):4711-23. DOI: 10.1021/acs.jmedchem.6b00052. View