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 (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. [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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