{{Short description|Investigational antineoplastic drug}} {{Use dmy dates|date=January 2025}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | image = Rebimastat.svg | image_class = skin-invert-image | width = | alt = | caption =
<!-- Clinical data --> | pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) --> | licence_EU = <!-- EMA uses INN (or special INN_EMA) --> | DailyMedID = <!-- DailyMed may use generic or brand name (generic name preferred) --> | licence_US = <!-- FDA may use generic or brand name (generic name preferred) --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | class = | ATCvet = | ATC_prefix = | ATC_supplemental =
<!-- Legal status --> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled --> | legal_AU_comment = | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> | legal_BR_comment = | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA_comment = | legal_DE = <!-- Anlage I, II, III or Unscheduled --> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> | legal_UK_comment = | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_US_comment = | legal_EU = | legal_EU_comment = | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> | legal_UN_comment = | legal_status =
<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =
<!-- Identifiers --> | CAS_number = 259188-38-0 | CAS_number2 = | CAS_supplemental = | PubChem = 9913881 | IUPHAR_ligand = | DrugBank = DB06573 | ChemSpiderID = 8089530 | UNII = 1B47R6ZX4K | KEGG = D03800 | ChEBI = | ChEMBL = 76222 | NIAID_ChemDB = | PDB_ligand = | synonyms = BMS-275291
<!-- Chemical and physical data --> | IUPAC_name = <nowiki>(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</nowiki> | C = 23 | H = 41 | N = 5 | O = 5 | S = 1 | SMILES = 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 | StdInChI = 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 | StdInChI_comment = | StdInChIKey = GTXSRFUZSLTDFX-HRCADAONSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }} '''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.<ref name="pmid39594665">{{cite journal |vauthors=Mayasin YP, Osinnikova MN, Kharisova CB, Kitaeva KV, Filin IY, Gorodilova AV, Kutovoi GI, Solovyeva VV, Golubev AI, Rizvanov AA |title=Extracellular Matrix as a Target in Melanoma Therapy: From Hypothesis to Clinical Trials |journal=Cells |volume=13 |issue=22 |date=November 2024 |page=1917 |pmid=39594665 |pmc=11592585 |doi=10.3390/cells13221917|doi-access=free }}</ref><ref name="pmid34157437">{{cite journal |vauthors=Das S, Amin SA, Jha T |title=Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies |journal=European Journal of Medicinal Chemistry |volume=223 |issue= |article-number=113623 |date=November 2021 |pmid=34157437 |doi=10.1016/j.ejmech.2021.113623}}</ref><ref name="pmid26852787">{{cite journal |vauthors=Yang JS, Lin CW, Su SC, Yang SF |title=Pharmacodynamic considerations in the use of matrix metalloproteinase inhibitors in cancer treatment |journal=Expert Opinion on Drug Metabolism & Toxicology |volume=12 |issue=2 |pages=191–200 |date=2016 |pmid=26852787 |doi=10.1517/17425255.2016.1131820}}</ref><ref name="pmid25376097">{{cite journal |vauthors=Vandenbroucke RE, Libert C |title=Is there new hope for therapeutic matrix metalloproteinase inhibition? |journal=Nature Reviews. Drug Discovery |volume=13 |issue=12 |pages=904–27 |date=December 2014 |pmid=25376097 |doi=10.1038/nrd4390}}</ref><ref name="pmid35893744">{{cite journal |vauthors=Gonçalves PR, Nascimento LD, Gerlach RF, Rodrigues KE, Prado AF |title=Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure |journal=Pharmaceuticals (Basel, Switzerland) |volume=15 |issue=8 |date=July 2022 |page=920 |pmid=35893744 |pmc=9331741 |doi=10.3390/ph15080920 |doi-access=free |url=}}</ref><ref name="Inxight">{{cite web |title=REBIMASTAT |website=Inxight Drugs |url=https://drugs.ncats.io/drug/1B47R6ZX4K |access-date=25 January 2025}}</ref>
==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.<ref name="pmid39594665"/><ref name="pmid34157437"/><ref name="pmid26852787"/><ref name="pmid25376097"/>
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.<ref name="pmid34157437"/><ref name="pmid25376097"/>
==History== Rebimastat was initially developed by Chiroscience (later part of Celltech Group plc) and subsequently by Bristol-Myers Squibb.<ref name="pmid34157437"/> 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.<ref name="pmid39594665"/>
==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.<ref name="pmid26852787"/><ref name="pmid25376097"/><ref name="Inxight"/>
However, clinical development was ultimately discontinued due to significant toxicity.<ref name="pmid35893744"/> 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.<ref name="pmid26852787"/><ref name="pmid34157437"/><ref name="pmid25376097"/><ref name="pmid35893744"/><ref name="Inxight"/>
==References== {{reflist}}
Category:Abandoned drugs Category:Experimental cancer drugs Category:Carboxamides Category:Lactams Category:Hydantoins Category:Hydrosulfides Category:Tert-butyl compounds