{{Short description|Experimental anticancer drug}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | image = ACBI3_structure.png | image_class = skin-invert-image | width = 300
<!-- Clinical data --> | tradename = | pregnancy_category = | routes_of_administration = | class = | ATC_prefix = | ATC_suffix = | ATC_supplemental =
<!-- Legal status --> | legal_status =
<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =
<!-- Identifiers --> | CAS_number = 2938169-76-5 | CAS_supplemental = | PubChem = 169449364 | IUPHAR_ligand = | DrugBank = | ChemSpiderID = 129422922 | UNII = | ChEMBL = | synonyms =
<!-- Chemical and physical data --> | IUPAC_name = (2S,4R)-1-[(2S)-2-[4-[4-[(3S)-4-[4-[5-[(4S)-2-amino-3-cyano-4-methyl-6,7-dihydro-5H-1-benzothiophen-4-yl]-1,2,4-oxadiazol-3-yl]pyrimidin-2-yl]-3-methyl-1,4-diazepan-1-yl]butoxy]triazol-1-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide | C = 50 | H = 62 | N = 14 | O = 6 | S = 2 | SMILES = C[C@H]1CN(CCCN1C2=NC=CC(=N2)C3=NOC(=N3)[C@]4(CCCC5=C4C(=C(S5)N)C#N)C)CCCCOC6=CN(N=N6)[C@@H](C(C)C)C(=O)N7C[C@@H](C[C@H]7C(=O)N[C@@H](CO)C8=CC=C(C=C8)C9=C(N=CS9)C)O | StdInChI = 1S/C50H62N14O6S2/c1-29(2)42(47(68)63-25-34(66)22-38(63)46(67)55-37(27-65)32-11-13-33(14-12-32)43-31(4)54-28-71-43)64-26-40(58-60-64)69-21-7-6-18-61-19-9-20-62(30(3)24-61)49-53-17-15-36(56-49)45-57-48(70-59-45)50(5)16-8-10-39-41(50)35(23-51)44(52)72-39/h11-15,17,26,28-30,34,37-38,42,65-66H,6-10,16,18-22,24-25,27,52H2,1-5H3,(H,55,67)/t30-,34+,37-,38-,42-,50-/m0/s1 | StdInChIKey = DQRZNYPHOWVXPQ-YDUPODKQSA-N }}
'''ACBI3''' is an experimental anticancer agent which is one of the first examples of a proteolysis targeting chimera (PROTAC) against the protein KRAS.
Being a PROTAC, it is a bifunctional molecule with two halves joined by a linker; one half binds to its target, KRAS which is a key driver in certain types of cancer, while the other half binds E3 ligase which triggers the cell's natural protein degradation mechanisms. This causes the KRAS protein to be degraded.
In early stage testing, it was able to target 13 of the 17 most common mutated forms of KRAS found in cancer cells, allowing selective targeting of a wide range of cancer types. While this particular molecule is still at an early developmental stage, it is an important proof of concept that KRAS can be targeted with a PROTAC.<ref name="Popow_2024">{{cite journal | vauthors = Popow J, Farnaby W, Gollner A, Kofink C, Fischer G, Wurm M, Zollman D, Wijaya A, Mischerikow N, Hasenoehrl C, Prokofeva P, Arnhof H, Arce-Solano S, Bell S, Boeck G, Diers E, Frost AB, Goodwin-Tindall J, Karolyi-Oezguer J, Khan S, Klawatsch T, Koegl M, Kousek R, Kratochvil B, Kropatsch K, Lauber AA, McLennan R, Olt S, Peter D, Petermann O, Roessler V, Stolt-Bergner P, Strack P, Strauss E, Trainor N, Vetma V, Whitworth C, Zhong S, Quant J, Weinstabl H, Kuster B, Ettmayer P, Ciulli A | title = Targeting cancer with small-molecule pan-KRAS degraders | journal = Science | location = New York, N.Y. | volume = 385 | issue = 6715 | pages = 1338–1347 | date = September 2024 | pmid = 39298590 | doi = 10.1126/science.adm8684 | bibcode = 2024Sci...385.1338P | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hamilton G, Eggerstorfer MT, Stickler S | title = Development of PROTACS degrading KRAS and SOS1 | journal = Oncology Research | date = 2024 | volume = 32 | issue = 8 | pages = 1257–1264 | doi = 10.32604/or.2024.051653 | pmid = 39055890 | pmc = 11267056 }}</ref><ref>{{cite journal | vauthors = Kumar H, Sobhia ME | title = Interplay of PROTAC Complex Dynamics for Undruggable Targets: Insights into Ternary Complex Behavior and Linker Design | journal = ACS Medicinal Chemistry Letters | volume = 15 | issue = 8 | pages = 1306–1318 | date = August 2024 | pmid = 39140051 | doi = 10.1021/acsmedchemlett.4c00189 | pmc = 11317996 }}</ref><ref>{{cite journal | vauthors = Li Y, Yang L, Li X, Zhang X | title = Inhibition of GTPase KRAS<sup>G12D</sup>: a review of patent literature | journal = Expert Opinion on Therapeutic Patents | volume = 34 | issue = 8 | pages = 701–721 | date = August 2024 | pmid = 38884569 | doi = 10.1080/13543776.2024.2369630 }}</ref>
== See also == * Adagrasib * K-Ras(G12C) inhibitor 6 * MRTX1133 * Olomorasib * RMC-9805 * Sotorasib * SD36
== References == {{reflist}}
Category:Proteolysis targeting chimeras Category:Experimental cancer drugs Category:Diazepanes Category:Oxadiazoles Category:Benzothiophenes Category:Pyrimidines Category:Triazoles Category:Pyrrolidines Category:Thiazoles Category:Carboxamides Category:Nitriles Category:Amines Category:Diols