Dactolisib

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]

Dactolisib
Ball-and-stick model of the BEZ235 molecule
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
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 checkY
    Key: JOGKUKXHTYWRGZ-UHFFFAOYSA-N checkY
  • 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).
☒N verify (what is checkY☒N ?)
Infobox references

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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