Tipifarnib: Difference between revisions

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			{{Short description\|Chemical compound}}
	{{Drugbox		{{Drugbox
			\| Verifiedfields = changed
	\| IUPAC_name = 6--4-(3-chlorophenyl)-1-methylquinolin-2(1''H'')-one
			\| Watchedfields = changed
	\| image = Tipifarnib.png
			\| verifiedrevid = 376279232
	\| CAS_number =
			\| IUPAC_name = (+)-6--4-(3-chlorophenyl)-1-methylquinolin-2-one
	\| CAS_supplemental =
			\| image = Tipifarnib.svg
	\| ATC_prefix = none

	\| ATC_suffix =
			<!--Clinical data-->
	\| ATC_supplemental =
			\| tradename =
	\| PubChem = 148193
	\| ~~DrugBank~~ =		\| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
			\| pregnancy_US = <!-- A / B / C / D / X -->
	\| chemical_formula =
			\| pregnancy_category =
			\| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
			\| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
			\| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
			\| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
			\| legal_status = Investigational
			\| routes_of_administration =

			<!--Pharmacokinetic data-->
			\| bioavailability =
			\| protein_bound =
			\| metabolism =
			\| elimination_half-life =
			\| excretion =

			<!--Identifiers-->
			\| CAS_number_Ref = {{cascite\|changed\|??}}
			\| CAS_number = 192185-72-1
			\| ATC_prefix = None
			\| ATC_suffix =
			\| ATC_supplemental =
			\| PubChem = 159324
			\| DrugBank_Ref = {{drugbankcite\|changed\|drugbank}}
			\| DrugBank = DB04960
			\| ChemSpiderID_Ref = {{chemspidercite\|changed\|chemspider}}
			\| ChemSpiderID = 140122
			\| UNII_Ref = {{fdacite\|changed\|FDA}}
			\| UNII = MAT637500A
			\| KEGG_Ref = {{keggcite\|changed\|kegg}}
			\| KEGG = D03720
			\| ChEBI = 141969
			\| ChEMBL_Ref = {{ebicite\|changed\|EBI}}
			\| ChEMBL = 289228
			\| IUPHAR_ligand = 8025

			<!--Chemical data-->
	\| C=27 \| H=22 \| Cl=2 \| N=4 \| O=1		\| C=27 \| H=22 \| Cl=2 \| N=4 \| O=1
	\| molecular_weight = ~~489.395 g/mol~~		\| molecular_weight =
			\| smiles = CN1C(=O)C=C(c2cccc(Cl)c2)c3cc(ccc13)(N)(c4ccc(Cl)cc4)c5cncn5C
	\| bioavailability =
			\| StdInChI_Ref = {{stdinchicite\|changed\|chemspider}}
	\| protein_bound =
			\| StdInChI = 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
	\| metabolism =
			\| StdInChIKey_Ref = {{stdinchicite\|changed\|chemspider}}
	\| elimination_half-life =
			\| StdInChIKey = PLHJCIYEEKOWNM-HHHXNRCGSA-N
	\| excretion =
			\| synonyms = R115777
	\| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
	\| pregnancy_US = <!-- A / B / C / D / X -->
	\| pregnancy_category=
	\| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
	\| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
	\| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
	\| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
	\| legal_status =
	\| routes_of_administration =
	}}		}}

			'''Tipifarnib''' (],<ref name="INN">{{cite web \| title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 46 \| url =https://www.who.int/medicines/publications/druginformation/innlists/RL46.pdf \| publisher = World Health Organization \| access-date = 16 November 2016}}</ref>{{rp\|213}} proposed trade name '''Zarnestra''') is a ]. 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.<ref>{{cite journal \| vauthors = Cox AD, Der CJ, Philips MR \| title = Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery? \| journal = Clinical Cancer Research \| volume = 21 \| issue = 8 \| pages = 1819–27 \| date = April 2015 \| pmid = 25878363 \| pmc = 4400837 \| doi = 10.1158/1078-0432.CCR-14-3214 }}</ref>
	'''Tipifarnib''' ('''Zarnestra''') is a ] that is being investigated in patients 65 years of age and older with newly diagnosed ] (AML). It is also being tested in clinical trials in patients in certain stages of breast cancer.<ref></ref>

			==History==
	The compound was discovered by and is under investigation by ], L.L.C, with registration number R115777.
			The compound was discovered by ], L.L.C, with registration number R115777.

			For treatment of progressive ]s associated with ], it passed phase I clinical trials but was suspended (NCT00029354) in phase II.<ref>{{ClinicalTrialsGov\|NCT00025454\|R115777 in Treating Patients With Advanced Solid Tumors}}</ref><ref>{{ClinicalTrialsGov\|NCT00029354\|R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas}}</ref>
	==Approval process==
	Tipifarnib was submitted to the FDA by ] for the treatment of AML in patients aged 65 and over with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on January 24, 2005.

			Tipifarnib was submitted to the ] by ] for the treatment of AML in patients aged 65 and over with a ] (NDA) to the FDA on January 24, 2005. In June 2005, the FDA issued a "not approvable" letter for tipifarnib.<ref>{{cite news \| title = Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Receives Not Approvable Letter From FDA for Tipifarnib Based on Phase II Data \| url = http://www.prnewswire.com/news-releases/johnson--johnson-pharmaceutical-research--development-llc-receives-not-approvable-letter-from-fda-for-tipifarnib-based-on-phase-ii-data-54993352.html \| access-date = 16 November 2016 \| agency = PR Newswire \| date = Jun 30, 2005}}</ref>
	In June 2005, the FDA issued a "not approvable" letter for tipifarnib.<ref></ref>

			Kura Oncology in-licensed tipifarnib from Janssen in 2014.<ref>{{cite web \|last1=Carroll \|first1=John \| name-list-style = vanc \|title=Kura sheds stealth mode with $60M for PhII cancer drug licensed from J&J {{!}} FierceBiotech \|url=https://www.fiercebiotech.com/r-d/kura-sheds-stealth-mode-60m-for-phii-cancer-drug-licensed-from-j-j \|website=www.fiercebiotech.com \|language=en \|date=12 March 2015}}</ref>
	==References==
	{{Reflist}}

			==Investigations==
	]
			===Cancer===
			The inhibitor is being investigated in patients with HRAS mutant head and neck cancer, ] (PTCL), ] (MDS), and ] (CMML).<ref>{{cite journal \| vauthors = Witzig TE, Tang H, Micallef IN, Ansell SM, Link BK, Inwards DJ, Porrata LF, Johnston PB, Colgan JP, Markovic SN, Nowakowski GS, Thompson CA, Allmer C, Maurer MJ, Gupta M, Weiner G, Hohl R, Kurtin PJ, Ding H, Loegering D, Schneider P, Peterson K, Habermann TM, Kaufmann SH \| display-authors = 6 \| title = Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas \| journal = Blood \| volume = 118 \| issue = 18 \| pages = 4882–9 \| date = November 2011 \| pmid = 21725056 \| pmc = 3208296 \| doi = 10.1182/blood-2011-02-334904 }}</ref><ref>{{ClinicalTrialsGov\|NCT02383927\|Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations}}</ref><ref>{{ClinicalTrialsGov\|NCT02464228\|Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)}}</ref><ref>{{ClinicalTrialsGov\|NCT02779777\|Tipifarnib in Subjects With Myelodysplastic Syndromes}}</ref><ref>{{ClinicalTrialsGov\|NCT02807272\|Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML)}}</ref> It was previously tested in clinical trials in patients in certain stages of breast cancer.<ref>{{cite journal \| vauthors = Sparano JA, Moulder S, Kazi A, Coppola D, Negassa A, Vahdat L, Li T, Pellegrino C, Fineberg S, Munster P, Malafa M, Lee D, Hoschander S, Hopkins U, Hershman D, Wright JJ, Kleer C, Merajver S, Sebti SM \| display-authors = 6 \| title = Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer \| journal = Clinical Cancer Research \| volume = 15 \| issue = 8 \| pages = 2942–8 \| date = April 2009 \| pmid = 19351752 \| pmc = 2785076 \| doi = 10.1158/1078-0432.CCR-08-2658 \| url = }}</ref> It was also investigated as a treatment for ].<ref>{{cite journal \| vauthors = Alsina M, Fonseca R, Wilson EF, Belle AN, Gerbino E, Price-Troska T, Overton RM, Ahmann G, Bruzek LM, Adjei AA, Kaufmann SH, Wright JJ, Sullivan D, Djulbegovic B, Cantor AB, Greipp PR, Dalton WS, Sebti SM \| display-authors = 6 \| title = Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma \| journal = Blood \| volume = 103 \| issue = 9 \| pages = 3271–7 \| date = May 2004 \| pmid = 14726402 \| doi = 10.1182/blood-2003-08-2764 \| doi-access = free }}</ref>

			===Progeria===
	{{Chemotherapeutic agents}}
			]
			It was shown on a mouse model of ] 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.<ref>{{cite journal \| vauthors = Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, Conneely KN, Qu X, San H, Ganesh SK, Chen X, Avallone H, Kolodgie FD, Virmani R, Nabel EG, Collins FS \| display-authors = 6 \| title = A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model \| journal = Proceedings of the National Academy of Sciences of the United States of America \| volume = 105 \| issue = 41 \| pages = 15902–7 \| date = October 2008 \| pmid = 18838683 \| pmc = 2562418 \| doi = 10.1073/pnas.0807840105 \| url = http://www.pnas.org/content/105/41/15902.full.pdf \| bibcode = 2008PNAS..10515902C \| doi-access = free }}</ref>
			{{clear left}}

			== References ==
	]
			{{Reflist}}

			{{Chemotherapeutic agents}}

			]
	{{antineoplastic-drug-stub}}
			]
	{{oncology-stub}}
			]
			]
			]
			]
			]

Latest revision as of 08:55, 9 September 2024

Chemical compound Pharmaceutical compound

Tipifarnib
Clinical data

Other names	R115777
ATC code	None
Legal status
Legal status	Investigational
Identifiers
IUPAC name (+)-6--4-(3-chlorophenyl)-1-methylquinolin-2-one
CAS Number	192185-72-1
PubChem CID	159324
IUPHAR/BPS	8025
DrugBank	DB04960
ChemSpider	140122
UNII	MAT637500A
KEGG	D03720
ChEBI	CHEBI:141969
ChEMBL	ChEMBL289228
CompTox Dashboard (EPA)	DTXSID5041140
Chemical and physical data
Formula	C₂₇H₂₂Cl₂N₄O
Molar mass	489.40 g·mol
3D model (JSmol)	Interactive image
SMILES CN1C(=O)C=C(c2cccc(Cl)c2)c3cc(ccc13)(N)(c4ccc(Cl)cc4)c5cncn5C
InChI 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 Key:PLHJCIYEEKOWNM-HHHXNRCGSA-N
(what is this?) (verify)

Tipifarnib (INN, 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.

History

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.

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.

Kura Oncology in-licensed tipifarnib from Janssen in 2014.

Investigations

Cancer

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). It was previously tested in clinical trials in patients in certain stages of breast cancer. It was also investigated as a treatment for multiple myeloma.

Progeria

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.

References

"International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 46" (PDF). World Health Organization. Retrieved 16 November 2016.
Cox AD, Der CJ, Philips MR (April 2015). "Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?". Clinical Cancer Research. 21 (8): 1819–27. doi:10.1158/1078-0432.CCR-14-3214. PMC 4400837. PMID 25878363.
Clinical trial number NCT00025454 for "R115777 in Treating Patients With Advanced Solid Tumors" at ClinicalTrials.gov
Clinical trial number NCT00029354 for "R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas" at ClinicalTrials.gov
"Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Receives Not Approvable Letter From FDA for Tipifarnib Based on Phase II Data". PR Newswire. Jun 30, 2005. Retrieved 16 November 2016.
Carroll J (12 March 2015). "Kura sheds stealth mode with $60M for PhII cancer drug licensed from J&J | FierceBiotech". www.fiercebiotech.com.
Witzig TE, Tang H, Micallef IN, Ansell SM, Link BK, Inwards DJ, et al. (November 2011). "Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas". Blood. 118 (18): 4882–9. doi:10.1182/blood-2011-02-334904. PMC 3208296. PMID 21725056.
Clinical trial number NCT02383927 for "Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations" at ClinicalTrials.gov
Clinical trial number NCT02464228 for "Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)" at ClinicalTrials.gov
Clinical trial number NCT02779777 for "Tipifarnib in Subjects With Myelodysplastic Syndromes" at ClinicalTrials.gov
Clinical trial number NCT02807272 for "Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia (CMML)" at ClinicalTrials.gov
Sparano JA, Moulder S, Kazi A, Coppola D, Negassa A, Vahdat L, et al. (April 2009). "Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer". Clinical Cancer Research. 15 (8): 2942–8. doi:10.1158/1078-0432.CCR-08-2658. PMC 2785076. PMID 19351752.
Alsina M, Fonseca R, Wilson EF, Belle AN, Gerbino E, Price-Troska T, et al. (May 2004). "Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma". Blood. 103 (9): 3271–7. doi:10.1182/blood-2003-08-2764. PMID 14726402.
Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, et al. (October 2008). "A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 105 (41): 15902–7. Bibcode:2008PNAS..10515902C. doi:10.1073/pnas.0807840105. PMC 2562418. PMID 18838683.

Intracellular chemotherapeutic agents / antineoplastic agents (L01)

SPs/MIs
(M phase)

Block microtubule assembly	Vinca alkaloids (Vinblastine Vincristine Vindesine Vinflunine Vinorelbine)
Block microtubule disassembly	Taxanes (Cabazitaxel Docetaxel Larotaxel Ortataxel Paclitaxel Tesetaxel) Epothilones (Ixabepilone)

DNA replication
inhibitor

DNA precursors/
antimetabolites
(S phase)

Folic acid	Dihydrofolate reductase inhibitor (Aminopterin Methotrexate Pemetrexed Pralatrexate) Thymidylate synthase inhibitor (Pemetrexed Raltitrexed)
Purine	Adenosine deaminase inhibitor (Pentostatin) Halogenated/ribonucleotide reductase inhibitors (Cladribine Clofarabine Fludarabine) Nelarabine Rabacfosadine Thiopurine (Mercaptopurine Tioguanine)
Pyrimidine	Thymidylate synthase inhibitor (Capecitabine Carmofur Doxifluridine Floxuridine Fluorouracil Tegafur (+gimeracil/oteracil)) DNA polymerase inhibitor (Cytarabine +daunorubicin) Ribonucleotide reductase inhibitor (Gemcitabine) Hypomethylating agent (Azacitidine Decitabine)
Deoxyribonucleotide	Ribonucleotide reductase inhibitor (Hydroxycarbamide)

Topoisomerase inhibitors
(S phase)

I	Camptotheca (Belotecan Camptothecin Cositecan Etirinotecan pegol Exatecan Gimatecan Irinotecan Lurtotecan Rubitecan Silatecan Topotecan)
II	Podophyllum (Etoposide Teniposide)
II+Intercalation	Anthracyclines (Aclarubicin Amrubicin Daunorubicin (+cytarabine) Doxorubicin Epirubicin Idarubicin Pirarubicin Valrubicin Zorubicin) Anthracenediones (Losoxantrone Mitoxantrone Pixantrone) Amsacrine Bisantrene Crisnatol Menogaril

Crosslinking of DNA
(CCNS)

Alkylating	Nitrogen mustards: Bendamustine Chlormethine Cyclophosphamide (Ifosfamide Trofosfamide) Chlorambucil Melphalan (Melphalan flufenamide) Prednimustine Uramustine Nitrosoureas: Carmustine Fotemustine Lomustine (Semustine) Nimustine Ranimustine Streptozocin Alkyl sulfonates: Busulfan (Mannosulfan Treosulfan) Aziridines: Carboquone Thiotepa Triaziquone Triethylenemelamine
Platinum-based	Carboplatin Cisplatin Dicycloplatin Nedaplatin Oxaliplatin Satraplatin
Nonclassical	Altretamine Hydrazines (Procarbazine) Etoglucid Mitobronitol Pipobroman Triazenes (Dacarbazine Mitozolomide Temozolomide)
Intercalation	Streptomyces (Dactinomycin Bleomycin Mitomycins Plicamycin)

Photosensitizers/PDT

Other

Enzyme inhibitors	FI (Tipifarnib) CDK inhibitors (Abemaciclib Alvocidib Palbociclib Ribociclib Seliciclib) PrI Bortezomib Carfilzomib Oprozomib Ixazomib PhI (Anagrelide) IMPDI (Tiazofurin) LI (Masoprocol) PARP inhibitor (Fuzuloparib Niraparib +abiraterone acetate Olaparib Rucaparib) HDAC (Belinostat Entinostat Panobinostat Romidepsin Vorinostat) PIKI (Pi3K) (Alpelisib Copanlisib Duvelisib Idelalisib Inavolisib Umbralisib) IDH (Enasidenib Ivosidenib Olutasidenib Vorasidenib)
Receptor antagonists	ERA (Atrasentan) Retinoid X receptor (Bexarotene) Sex steroid (Testolactone)
Other/ungrouped	Adagrasib Aflibercept Arsenic trioxide Asparagine depleters (Asparaginase/Pegaspargase) Axicabtagene ciloleucel Belzutifan Bexarotene Brexucabtagene autoleucel Celecoxib Ciltacabtagene autoleucel Demecolcine Denileukin diftitox Eflornithine Elesclomol Elsamitrucin Epacadostat Eribulin Estramustine Glasdegib Idecabtagene vicleucel Imetelstat Lifileucel Lisocabtagene maraleucel Lonidamine Lucanthone Lurbinectedin Mitoguazone Mitotane Nadofaragene firadenovec Navitoclax Obecabtagene autoleucel Oblimersen Omacetaxine mepesuccinate Plitidepsin Tabelecleucel Retinoids (Alitretinoin Tretinoin) Selinexor Sitimagene ceradenovec Sotorasib Tagraxofusp Talimogene laherparepvec Tazemetostat Tebentafusp Tiazofurine Tigilanol tiglate Tisagenlecleucel Trabectedin Veliparib Venetoclax Verdinexor Vosaroxin

WHO-EM
Withdrawn from market
Clinical trials:
- Phase III
- Never to phase III

Categories: