Tipifarnib

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Tipifarnib
File:Tipifarnib.svg
Clinical data
Other namesR115777
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
  • (+)-6-[(R)-Amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
CompTox Dashboard (EPA)
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Chemical and physical data
FormulaC27H22Cl2N4O
Molar mass489.40 g·mol−1
3D model (JSmol)
  • CN1C(=O)C=C(c2cccc(Cl)c2)c3cc(ccc13)[C@](N)(c4ccc(Cl)cc4)c5cncn5C
  • InChI=1S/C27H22Cl2N4O/c1-32-16-31-15-25(32)27(30,18-6-9-20(28)10-7-18)19-8-11-24-23(13-19)22(14-26(34)33(24)2)17-4-3-5-21(29)12-17/h3-16H,30H2,1-2H3/t27-/m1/s1 ☒N
  • Key:PLHJCIYEEKOWNM-HHHXNRCGSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Tipifarnib (INN,[1]: 213  proposed trade name Zarnestra) is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.[2]

History

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The compound was discovered by Johnson & Johnson Pharmaceutical Research & Development, L.L.C, with registration number R115777.

For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, it passed phase I clinical trials but was suspended (NCT00029354) in phase II.[3][4]

Tipifarnib was submitted to the FDA by Johnson & Johnson for the treatment of AML in patients aged 65 and over with a new drug application (NDA) to the FDA on January 24, 2005. In June 2005, the FDA issued a "not approvable" letter for tipifarnib.[5]

Kura Oncology in-licensed tipifarnib from Janssen in 2014.[6]

Investigations

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Cancer

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The inhibitor is being investigated in patients with HRAS mutant head and neck cancer, peripheral T-cell lymphoma (PTCL), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).[7][8][9][10][11] It was previously tested in clinical trials in patients in certain stages of breast cancer.[12] It was also investigated as a treatment for multiple myeloma.[13]

Progeria

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File:Progeria20132-300.jpg
Confocal microscopy photographs of the descending aortas of two 15-month-old progeria mice, one untreated (left picture) and the other treated with the farnsyltransferase inhibitor drug tipifarnib (right picture). The microphotographs show prevention of the vascular smooth muscle cell loss that is otherwise rampant by this age. Staining was smooth muscle alpha-actin (green), lamins A/C (red) and DAPI (blue). (Original magnification, ×40)

It was shown on a mouse model of Hutchinson–Gilford progeria syndrome that dose-dependent administration of tipifarnib can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease.[14]

References

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  3. ^ Clinical trial number NCT00025454 for "R115777 in Treating Patients With Advanced Solid Tumors" at ClinicalTrials.gov
  4. ^ Clinical trial number NCT00029354 for "R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas" at ClinicalTrials.gov
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  8. ^ Clinical trial number NCT02383927 for "Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations" at ClinicalTrials.gov
  9. ^ Clinical trial number NCT02464228 for "Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)" at ClinicalTrials.gov
  10. ^ Clinical trial number NCT02779777 for "Tipifarnib in Subjects With Myelodysplastic Syndromes" at ClinicalTrials.gov
  11. ^ Clinical trial number NCT02807272 for "Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML)" at ClinicalTrials.gov
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