Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity

Overview

Journal Mol Cancer Ther

Date 2024 Mar 26

PMID 38530115

Authors

Peter Cornelius

Benjamin A Mayes

John S Petersen

David J Turnquist

Pierre J Dufour

Andrew J Dannenberg

James M Shanahan

Bradley J Carver

Affiliations

Soon will be listed here.

Abstract

Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel METAP2 inhibitor (METAP2i) SDX-7539. In vitro binding, enzyme, and cell-based assays demonstrated that SDX-7539 is a potent and selective METAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, METAP2i SDX-7539, limitations observed with prior generation, small molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the METAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a phase I clinical safety study in patients with late-stage cancer and is currently being evaluated in multiple phase Ib/II clinical studies in patients with advanced solid tumors.

References

Guruceaga X, Perez-Cuesta U, Abad-Diaz de Cerio A, Gonzalez O, Alonso R, Hernando F . Fumagillin, a Mycotoxin of : Biosynthesis, Biological Activities, Detection, and Applications. Toxins (Basel). 2019; 12(1). PMC: 7020470. DOI: 10.3390/toxins12010007. View

Farrell P, Zopf C, Huang H, Balakrishna D, Holub C, Bilakovics J . Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors. J Pharmacol Exp Ther. 2019; 371(2):299-308. DOI: 10.1124/jpet.119.259028. View

Zhong Y, Shao L, Li Y . Cathepsin B-cleavable doxorubicin prodrugs for targeted cancer therapy (Review). Int J Oncol. 2013; 42(2):373-83. PMC: 3583876. DOI: 10.3892/ijo.2012.1754. View

Satchi-Fainaro R, Puder M, Davies J, Tran H, Sampson D, Greene A . Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat Med. 2004; 10(3):255-61. DOI: 10.1038/nm1002. View

Datta B . Roles of P67/MetAP2 as a tumor suppressor. Biochim Biophys Acta. 2009; 1796(2):281-92. DOI: 10.1016/j.bbcan.2009.08.002. View

Kanno T, Endo H, Takeuchi K, Morishita Y, Fukayama M, Mori S . High expression of methionine aminopeptidase type 2 in germinal center B cells and their neoplastic counterparts. Lab Invest. 2002; 82(7):893-901. DOI: 10.1097/01.lab.0000020419.25365.c4. View

Selvakumar P, Lakshmikuttyamma A, Kanthan R, Kanthan S, Dimmock J, Sharma R . High expression of methionine aminopeptidase 2 in human colorectal adenocarcinomas. Clin Cancer Res. 2004; 10(8):2771-5. DOI: 10.1158/1078-0432.ccr-03-0218. View

Sundberg T, Darricarrere N, Cirone P, Li X, McDonald L, Mei X . Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37. Chem Biol. 2011; 18(10):1300-11. PMC: 3205358. DOI: 10.1016/j.chembiol.2011.07.020. View

Hannig G, Bernier S, Hoyt J, Doyle B, Clark E, Karp R . Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI-2458. Arthritis Rheum. 2007; 56(3):850-60. DOI: 10.1002/art.22402. View

10.

Javia A, Vanza J, Bardoliwala D, Ghosh S, Misra L, Patel M . Polymer-drug conjugates: Design principles, emerging synthetic strategies and clinical overview. Int J Pharm. 2022; 623:121863. DOI: 10.1016/j.ijpharm.2022.121863. View

11.

Xie J, Rice M, Chen Z, Cheng Y, Hsu E, Chen M . Imaging of Methionine Aminopeptidase II for Prostate Cancer Risk Stratification. Cancer Res. 2021; 81(9):2510-2521. PMC: 8137584. DOI: 10.1158/0008-5472.CAN-20-2969. View

12.

Warder S, Tucker L, McLoughlin S, Strelitzer T, Meuth J, Zhang Q . Discovery, identification, and characterization of candidate pharmacodynamic markers of methionine aminopeptidase-2 inhibition. J Proteome Res. 2008; 7(11):4807-20. DOI: 10.1021/pr800388p. View

13.

Liu S, Widom J, Kemp C, Crews C, Clardy J . Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science. 1998; 282(5392):1324-7. DOI: 10.1126/science.282.5392.1324. View

14.

Yuan F, Quan L, Cui L, Goldring S, Wang D . Development of macromolecular prodrug for rheumatoid arthritis. Adv Drug Deliv Rev. 2012; 64(12):1205-19. PMC: 3572768. DOI: 10.1016/j.addr.2012.03.006. View

15.

Selvakumar P, Lakshmikuttyamma A, Dimmock J, Sharma R . Methionine aminopeptidase 2 and cancer. Biochim Biophys Acta. 2006; 1765(2):148-54. DOI: 10.1016/j.bbcan.2005.11.001. View

16.

Kopecek J, Kopeckova P . HPMA copolymers: origins, early developments, present, and future. Adv Drug Deliv Rev. 2009; 62(2):122-49. PMC: 2836498. DOI: 10.1016/j.addr.2009.10.004. View

17.

Lee H, Choi W, Son H, Lee S, Kim J, Ahn S . Absorption, distribution, metabolism, and excretion of CKD-732, a novel antiangiogenic fumagillin derivative, in rats, mice, and dogs. Arch Pharm Res. 2004; 27(2):265-72. DOI: 10.1007/BF02980116. View

18.

Logothetis C, Wu K, Finn L, Daliani D, Figg W, Ghaddar H . Phase I trial of the angiogenesis inhibitor TNP-470 for progressive androgen-independent prostate cancer. Clin Cancer Res. 2001; 7(5):1198-203. View

19.

Jain R . Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014; 26(5):605-22. PMC: 4269830. DOI: 10.1016/j.ccell.2014.10.006. View

20.

Kusaka M, Sudo K, Matsutani E, Kozai Y, Marui S, Fujita T . Cytostatic inhibition of endothelial cell growth by the angiogenesis inhibitor TNP-470 (AGM-1470). Br J Cancer. 1994; 69(2):212-6. PMC: 1968693. DOI: 10.1038/bjc.1994.41. View