Drug Information

Drug (ID: DG01475) and It's Reported Resistant Information

• Name: Lonafarnib
• Synonyms: Lonafarnib; 193275-84-2; Sarasar; Sch66336; Sch 66336; Sch-66336; UNII-IOW153004F; CHEMBL298734; IOW153004F; (R)-4-(2-(4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl)-2-oxoethyl)piperidine-1-carboxamide; 1-PIPERIDINECARBOXAMIDE, 4-[2-[4-[(11R)-3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-B]PYRIDIN-11-YL]-1-PIPERIDINYL]-2-OXOETHYL]-; 4-[2-[4-(6,15-Dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide; 4-[2-[4-[(2R)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl]piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide; Zokinvy; 1-Piperidinecarboxamide, 4-(2-(4-((11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-1-piperidinyl)-2-oxoethyl)-; 4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]piperidin-1-yl}-2-oxoethyl)piperidine-1-carboxamide; SMR004701448; Lonafarnib (USAN/INN); Lonafarnib [USAN:INN]; C27H31Br2ClN4O2; Lonafarnib (SCH66336); lonafarnibum; 4-(2-(4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide; SCH-066336; 4-[2-[4-[(11R)-3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide; 1o5m; (non-labelled)Lonafarnib-d9; SCHEMBL19032; Sarasar; ; ; SCH 66336; (+)-4-(2-(4-(11R)-3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-piperidin-1-yl))-2-oxoethyl)-piperidine-1-carboxamide; MLS006010423; MLS006011106; GTPL8024; Lonafarnib, >=98% (HPLC); BDBM14459; CHEBI:47097; DTXSID90172927; BCP07027; EX-A1630; ZINC3950115; NSC719467; s2797; AKOS005145760; CCG-270312; CS-0792; DB06448; NSC-719467; NCGC00346707-01; 1-Piperidinecarboxamide, 4-(2-(4-((11R-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-1-piperidinyl)-2-oxoethyl)-; AC-32661; AS-56182; HY-15136; SW220034-1; Y0240; C73675; D04768; J-514232; Q3258910; (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidin-yl]-2-oxo-ethyl]-1-piperidinecarboxamide; (+)-4[2-[4-(8-Chloro-3,11-dihydro-5H-benzo[5,6] cyclohepta[1,2-b]-pyridin-11(R)-yl-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide; 4-(2-{4-[(2R)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3,5,7,12,14-hexaen-2-yl]piperidin-1-yl}-2-oxoethyl)piperidine-1-carboxamide; 4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[1,2]cyclohepta[2,4-b]pyridin-11-yl]piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide; 4-[2-[4-[(11R)-3,10-Dibromo-8-chloro-6,11-dihydro-5h-Benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-Piperidinyl]-2-oxoethyl]-1-Piperidi necarboxamide
• Indication:
  In total 1 Indication(s)
  Human immunodeficiency virus infection [ICD-11: 1C60-1C62]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Ovarian cancer [ICD-11: 2C73]; [1]
• Target: Human immunodeficiency virus Protease (HIV PR); POL_HV1B1; [1]
• Formula: 3
• IsoSMILES: C1CN(CCC1CC(=O)N2CCC(CC2)[C@@H]3C4=C(CCC5=C3N=CC(=C5)Br)C=C(C=C4Br)Cl)C(=O)N
• InChI: InChI=1S/C27H31Br2ClN4O2/c28-20-12-19-2-1-18-13-21(30)14-22(29)24(18)25(26(19)32-15-20)17-5-9-33(10-6-17)23(35)11-16-3-7-34(8-4-16)27(31)36/h12-17,25H,1-11H2,(H2,31,36)/t25-/m1/s1
• InChIKey: DHMTURDWPRKSOA-RUZDIDTESA-N
• PubChem CID: 148195
• ChEBI ID: CHEBI:47097
• TTD Drug ID: D07IQS
• VARIDT ID: DR1861
• DrugBank ID: DB06448

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: GTPase Nras (NRAS) [2]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CHLA-15 cells; Brain; Homo sapiens (Human); CVCL_6594
• In Vitro Model: CHLA-20 cells; Brain; Homo sapiens (Human); CVCL_6602
• In Vitro Model: CHLA-90 cells; Brain; Homo sapiens (Human); CVCL_6610
• In Vitro Model: CHLA-95 cells; Brain; Homo sapiens (Human); CVCL_6611
• In Vitro Model: CHLA-171 cells; Brain; Homo sapiens (Human); CVCL_6597
• In Vitro Model: COG-N-426 cells; Brain; Homo sapiens (Human); CVCL_LF58
• In Vitro Model: COG-N-415 cells; Brain; Homo sapiens (Human); CVCL_AQ23
• In Vitro Model: COG-N-557 cells; Brain; Homo sapiens (Human); CVCL_0389
• In Vitro Model: LA-N-5 cells; Brain; Homo sapiens (Human); CVCL_0389
• In Vitro Model: LA-N-6 cells; Bone marrow; Homo sapiens (Human); CVCL_1363
• In Vitro Model: NB-1643 cells; Adrenal; Homo sapiens (Human); CVCL_5627
• In Vitro Model: NB-EBC1 cells; Brain; Homo sapiens (Human); CVCL_E218
• In Vitro Model: SK-N-FI cells; Brain; Homo sapiens (Human); CVCL_1702
• In Vitro Model: SMS-LHN cells; Brain; Homo sapiens (Human); CVCL_9539
• In Vitro Model: CHP-134 cells; Adrenal gland; Homo sapiens (Human); CVCL_1124
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: LA-N-1 cells; Brain; Homo sapiens (Human); CVCL_1827
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: GI-ME-N cells; Brain; Homo sapiens (Human); CVCL_1232
• In Vitro Model: NBL-S cells; Brain; Homo sapiens (Human); CVCL_2136
• In Vitro Model: NGP cells; Lung; Homo sapiens (Human); CVCL_2141
• In Vivo Model: NSG mice model; Mus musculus
• Experiment for Molecule Alteration: PCR; RNA and miRNA extraction assay; RT-qPCR; Gene expression analysis; Immunoblotting assay; Dual-luciferase assay; Immunohistochemistry
• Experiment for Drug Resistance: Cell viability assay; Synergy assay; Cell cycle assay; Apoptosis assay; Magnetic resonance imaging assay
• Mechanism Description: Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

Ovarian cancer [ICD-11: 2C73]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Protein farnesyltransferase subunit beta (FNTB) [1]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Noncoding; (c.7-17904G>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: electrophoretic-mobility-shift assay; luciferase-reporter assay; RT-qPCR

References

• Ref 1: The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patientsBr J Clin Pharmacol. 2015 Nov;80(5):1139-48. doi: 10.1111/bcp.12688. Epub 2015 Jul 22.
• Ref 2: Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma. Nat Commun. 2024 Apr 23;15(1):3422.