Dactolisib

Last updated
Dactolisib
Dactolisib.svg
Dactolisib molecule ball.png
Names
Preferred IUPAC name
2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile
Other names
NVP-BEZ235; BEZ-235; RTB101
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C30H23N5O/c1-30(2,18-31)22-9-11-23(12-10-22)35-28-24-15-19(21-14-20-6-4-5-7-25(20)32-16-21)8-13-26(24)33-17-27(28)34(3)29(35)36/h4-17H,1-3H3 Yes check.svgY
    Key: JOGKUKXHTYWRGZ-UHFFFAOYSA-N Yes check.svgY
  • N#CC(c6ccc(N5c4c(cnc3ccc(c1cc2ccccc2nc1)cc34)N(C5=O)C)cc6)(C)C
Properties
C30H23N5O
Molar mass 469.548 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Dactolisib (codenamed NVP-BEZ235 and BEZ-235, also known as RTB101) is an imidazoquinoline derivative acting as a PI3K inhibitor. [1] It also inhibits mTOR. [2] It is being investigated as a possible cancer treatment. [3]

It has been shown to be toxic to Waldenström's macroglobulinemia cells. [4]

It was the first PI3K inhibitor to enter clinical trials, in 2006. [5]

A phase IB/II clinical trial for locally advanced or metastatic HER2 negative breast cancer has completed. [6]

A phase II clinical trial for advanced pancreatic neuroendocrine tumors (pNET) had initially reported results, but was later terminated because insufficient normal tissue tolerance to the drug. [7] A phase I clinical trial of BEZ235 in patients with advanced renal cell carcinoma had to be terminated prematurely due to toxicity and a lack of clinical efficacy . [8] Another Phase Ib study on patients with various solid cancers found severe normal tissue toxicity as well when BEZ235/Dactolisib was administered in combination with the mTOR inhibitor Everolimus. The authors concluded that the combination of both drugs demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity . [9] A phase I study of BEZ-235 to treat acute lymphoid leukaemia was initiated in 2012, but no results were published since then. [10]

A phase 2a randomized, placebo-controlled clinical trial published in 2018 showed that everolimus in combination with dactolisib decreased the rate of reported infections in an elderly population. [11]

References

  1. ↑ Liu, TJ; Koul, D; LaFortune, T; Tiao, N; Shen, RJ; Maira, SM; Garcia-Echevrria, C; Yung, WKA (11 August 2009). "NVP-BEZ235, a Novel Dual Phosphatidylinositol 3-kinase/Mammalian Target of Rapamycin Inhibitor, Elicits Multifaceted Antitumor Activities in Human Gliomas". Molecular Cancer Therapeutics. 8 (8): 2204–10. doi:10.1158/1535-7163.MCT-09-0160. PMC   2752877 . PMID   19671762.
  2. ↑ Awasthi, N; Yen, PL; Schwarz, MA; Schwarz, RE (March 2012). "The Efficacy of a Novel, Dual PI3K/mTOR Inhibitor NVP-BEZ235 to Enhance Chemotherapy and Antiangiogenic Response in Pancreatic Cancer". Journal of Cellular Biochemistry. 113 (3): 784–91. doi:10.1002/jcb.23405. PMID   22020918. S2CID   23005922.
  3. ↑ Maira, SM; Stauffer, F; Schnell, C; García-Echeverría, C (1 February 2009). "PI3K Inhibitors for Cancer Treatment: Where Do We Stand?". Biochemical Society Transactions. 37 (1): 265–72. doi:10.1042/BST0370265. PMID   19143644.
  4. ↑ Sacco, A; Roccaro, A; Ghobrial, IM (November 2010). "Role of Dual PI3/Akt and mTOR Inhibition in Waldenström's Macroglobulinemia". Oncotarget. 1 (7): 578–82. doi:10.18632/oncotarget.192. PMC   3248138 . PMID   21317453.
  5. ↑ "A Phase I/II Study of BEZ235 in Patients with Advanced Solid Malignancies Enriched by Patients with Advanced Breast Cancer". ClinicalTrials.gov. Retrieved 16 July 2016.
  6. ↑ Phase Ib/II Trial of BEZ235 With Paclitaxel in Patients With HER2 Negative, Locally Advanced or Metastatic Breast Cancer
  7. ↑ BEZ235 Phase II Trial in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET) After Failure of mTOR Inhibitor Therapy.
  8. ↑ Pongas, G.; Fojo, T. (2016). "BEZ235: When Promising Science Meets Clinical Reality". The Oncologist. 21 (9): 1033–1034. doi:10.1634/theoncologist.2016-0243. PMC   5016067 . PMID   27566248.
  9. ↑ "A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib(BEZ235) Combined with Everolimus in Patients with AdvancedSolid Malignancies". Target Oncology. Retrieved 29 March 2017.
  10. ↑ "A Phase I, Dose-finding Study of BEZ235 in Adult Patients With Relapsed or Refractory Acute Leukemia". clinicatrials.gov. Retrieved 29 July 2020.
  11. ↑ Zhavoronkov A (2020). "Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections". Aging . 12 (8): 6492–6510. doi:10.18632/aging.102988. PMC   7202545 . PMID   32229705.


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