Rebimastat

Last updated

Rebimastat
Rebimastat.svg
Clinical data
Other namesBMS-275291
Routes of
administration 		By mouth
Identifiers
  • (2S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-4-methyl-2-[[(2S)-2-sulfanyl-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)butanoyl]amino]pentanamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C23H41N5O5S
Molar mass 499.67 g·mol−1
3D model (JSmol)
  • CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](S)CCN1C(=O)N(C)C(C)(C)C1=O)C(C)(C)C
  • InChI=1S/C23H41N5O5S/c1-13(2)12-14(17(29)26-16(19(31)24-8)22(3,4)5)25-18(30)15(34)10-11-28-20(32)23(6,7)27(9)21(28)33/h13-16,34H,10-12H2,1-9H3,(H,24,31)(H,25,30)(H,26,29)/t14-,15-,16+/m0/s1
  • Key:GTXSRFUZSLTDFX-HRCADAONSA-N

Rebimastat is an abandoned investigational antineoplastic drug developed as a broad-spectrum matrix metalloproteinase inhibitor (MMPI). It was designed to target enzymes implicated in cancer progression, aiming to reduce tumor growth and metastasis. Although promising in preclinical studies, clinical development was halted due to adverse effects. [1] [2] [3] [4] [5] [6]

Contents

Pharamcology

Rebimastat is a second-generation, sulfhydryl-based MMPI that binds to the catalytic zinc ion within the active site of several matrix metalloproteinases (MMPs), including MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14. MMPs are zinc-dependent endopeptidases that play a crucial role in the degradation of the extracellular matrix (ECM). This ECM remodeling is essential for various physiological processes, but in cancer, it facilitates angiogenesis (formation of new blood vessels), tumor invasion, and metastasis (spread of cancer cells to distant sites). By inhibiting these MMPs, rebimastat aimed to disrupt these processes, potentially limiting tumor growth and spread by reducing blood supply and hindering tumor cell proliferation. [1] [2] [3] [4]

As one of the earlier non-hydroxamate MMPIs, rebimastat incorporates a thiol zinc-binding group. This design aimed to achieve broad-spectrum MMP inhibition while minimizing inhibition of sheddases (also known as ADAMs), metalloproteinases responsible for shedding membrane-bound proteins. This "sheddase-sparing" approach was intended to mitigate some of the side effects observed with earlier MMP inhibitors, which were thought to be related to the inhibition of these other metalloproteinases. [2] [4]

History

Rebimastat was initially developed by Chiroscience (later part of Celltech Group plc) and subsequently by Bristol-Myers Squibb. [2] Preclinical studies demonstrated rebimastat's potential, showing dose-dependent inhibition of angiogenesis and tumor metastasis in models such as the B16-BL6 metastatic melanoma cell line and the in vivo Matrigel plug cell migration assay. It also inhibited tumor progression in other rodent tumor models. [1]

Clinical trials

Clinical trials evaluated rebimastat's efficacy and safety in various cancers, including prostate cancer, HIV-related Kaposi's sarcoma, non-small cell lung cancer (NSCLC), and breast cancer. These included multiple phase II trials and at least one phase III trial. [3] [4] [6]

However, clinical development was ultimately discontinued due to significant toxicity. [5] Phase II trials in early-stage breast cancer and a phase III trial in NSCLC, where rebimastat was used as adjuvant therapy, were halted because patients experienced arthralgia (joint pain), a side effect consistent with MMP inhibitor-induced musculoskeletal toxicity. Other reported adverse effects included myalgia (muscle pain), skin rash, fatigue, nausea, headache, and taste alterations. The observed toxicity profile, coupled with a lack of significant clinical benefit, led to the termination of rebimastat's clinical development. [3] [2] [4] [5] [6]

References

  1. 1 2 3 Mayasin YP, Osinnikova MN, Kharisova CB, Kitaeva KV, Filin IY, Gorodilova AV, et al. (November 2024). "Extracellular Matrix as a Target in Melanoma Therapy: From Hypothesis to Clinical Trials". Cells. 13 (22): 1917. doi: 10.3390/cells13221917 . PMC   11592585 . PMID   39594665.
  2. 1 2 3 4 5 Das S, Amin SA, Jha T (November 2021). "Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies". European Journal of Medicinal Chemistry. 223 113623. doi:10.1016/j.ejmech.2021.113623. PMID   34157437.
  3. 1 2 3 4 Yang JS, Lin CW, Su SC, Yang SF (2016). "Pharmacodynamic considerations in the use of matrix metalloproteinase inhibitors in cancer treatment". Expert Opinion on Drug Metabolism & Toxicology. 12 (2): 191–200. doi:10.1517/17425255.2016.1131820. PMID   26852787.
  4. 1 2 3 4 5 Vandenbroucke RE, Libert C (December 2014). "Is there new hope for therapeutic matrix metalloproteinase inhibition?". Nature Reviews. Drug Discovery. 13 (12): 904–27. doi:10.1038/nrd4390. PMID   25376097.
  5. 1 2 3 Gonçalves PR, Nascimento LD, Gerlach RF, Rodrigues KE, Prado AF (July 2022). "Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure". Pharmaceuticals (Basel, Switzerland). 15 (8): 920. doi: 10.3390/ph15080920 . PMC   9331741 . PMID   35893744.
  6. 1 2 3 "REBIMASTAT". Inxight Drugs. Retrieved 25 January 2025.
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