ACBI3

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ACBI3
ACBI3 structure.png
Identifiers
  • (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
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C50H62N14O6S2
Molar mass 1019.26 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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
  • Key:DQRZNYPHOWVXPQ-YDUPODKQSA-N

ACBI3 is an experimental anticancer drug which is one of the first examples of a proteolysis targeting chimera or PROTAC. It is a bifunctional molecule with two halves joined by a linker; one half binds to a protein found in various forms of cancer cell called Kirsten rat sarcoma virus or KRAS, while the other half binds E3 ligase which triggers the cell's natural protein degradation mechanisms so that the entire complex is broken down. 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 and may be unlikely to be approved as a medicine itself, it is an important proof of concept which is likely to lead to the development of a range of related PROTAC type anticancer drugs. [1] [2] [3] [4]

See also

References

  1. ↑ Popow J, Farnaby W, Gollner A, Kofink C, Fischer G, Wurm M, et al. (September 2024). "Targeting cancer with small-molecule pan-KRAS degraders". Science. 385 (6715). New York, N.Y.: 1338–1347. Bibcode:2024Sci...385.1338P. doi: 10.1126/science.adm8684 . PMID   39298590.
  2. ↑ Hamilton G, Eggerstorfer MT, Stickler S (2024). "Development of PROTACS degrading KRAS and SOS1". Oncology Research. 32 (8): 1257–1264. doi:10.32604/or.2024.051653. PMC   11267056 . PMID   39055890.
  3. ↑ Kumar H, Sobhia ME (August 2024). "Interplay of PROTAC Complex Dynamics for Undruggable Targets: Insights into Ternary Complex Behavior and Linker Design". ACS Medicinal Chemistry Letters. 15 (8): 1306–1318. doi:10.1021/acsmedchemlett.4c00189. PMC   11317996 . PMID   39140051.
  4. ↑ Li Y, Yang L, Li X, Zhang X (August 2024). "Inhibition of GTPase KRASG12D: a review of patent literature". Expert Opinion on Therapeutic Patents. 34 (8): 701–721. doi:10.1080/13543776.2024.2369630. PMID   38884569.
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