Dactolisib

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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
IUPHAR/BPS
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 ?)

Dactolisib (codenamed NVP-BEZ235 and BEZ-235, also known as RTB101) is an

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. PMID 19671762
    .
  2. S2CID 23005922
    .
  3. PMID 19143644
    .
  4. 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. 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. PMID 32229705
    .


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