Drug Information

Drug (ID: DG01286) and It's Reported Resistant Information
Name
MK-1439
Synonyms
Doravirine; 1338225-97-0; MK-1439; Pifeltro; 3-chloro-5-[1-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)pyridin-3-yl]oxybenzonitrile; MK1439; UNII-913P6LK81M; 3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile; Doravirine (MK-1439); 913P6LK81M; 3-Chloro-5-({1-[(4-Methyl-5-Oxo-4,5-Dihydro-1h-1,2,4-Triazol-3-Yl)methyl]-2-Oxo-4-(Trifluoromethyl)-1,2-Dihydropyridin-3-Yl}oxy)benzonitrile; Doravirine [USAN:INN]; 4ncg; Pifeltro (TN); MK 1439; Doravirine, MK-1439; Doravirine; MK-1439; MK-1439(Doravirine); C17H11ClF3N5O3; Doravirine (JAN/USAN/INN); Mk-1439a; SCHEMBL2509885; CHEMBL2364608; DTXSID30158386; AMY16781; BCP02296; EX-A1968; BDBM50508293; MFCD22417167; s6492; ZINC72317283; AKOS030528603; CS-5924; DB12301; SB17104; NCGC00508866-01; AC-33637; HY-16767; DB-091410; D10624; F53303; A856128; Q6885419; S900006160; 2KW; 3-chloro-5-[[1-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-3-pyridyl]oxy]benzonitrile; Benzonitrile, 3-chloro-5-((1-((4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl)-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl)oxy)-
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Indication
In total 2 Indication(s)
Human immunodeficiency virus infection [ICD-11: 1C60-1C62]
Approved
[1]
Human immunodeficiency virus infection [ICD-11: 1C60-1C62]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
HIV infection [ICD-11: 1C62]
[1]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
HIV infection [ICD-11: 1C62]
[2]
Target Human immunodeficiency virus Reverse transcriptase (HIV RT) POL_HV1B1 [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C17H11ClF3N5O3
IsoSMILES
CN1C(=NNC1=O)CN2C=CC(=C(C2=O)OC3=CC(=CC(=C3)C#N)Cl)C(F)(F)F
InChI
1S/C17H11ClF3N5O3/c1-25-13(23-24-16(25)28)8-26-3-2-12(17(19,20)21)14(15(26)27)29-11-5-9(7-22)4-10(18)6-11/h2-6H,8H2,1H3,(H,24,28)
InChIKey
ZIAOVIPSKUPPQW-UHFFFAOYSA-N
PubChem CID
58460047
TTD Drug ID
D0R0TS
INTEDE ID
DR0533
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-01: Infectious/parasitic diseases
Click to Show/Hide the Resistance Disease of This Class
HIV infection [ICD-11: 1C62]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: HIV1 Reverse transcriptase (HIV1 RT) [1]
Resistant Disease Human immunodeficiency virus infection [ICD-11: 1C62.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Y188L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model AIP KO MEF cells Skin Mus musculus (Mouse) CVCL_UJ02
MT4 cells Umbilical cord blood Homo sapiens (Human) CVCL_2632
Experiment for
Molecule Alteration		 PCR
Mechanism Description The cyanochlorophenol moiety forms pai-pai stacking with Y188, and the Y188L substitution eliminates the pai-pai interactions and creates a clash with DOR; thus, the Y188L substitution confers significant resistance to DOR, suggesting that the pai-pai interactions between the residues are crucial for the binding of DOR to RT.
Key Molecule: Reverse transcriptase (RT) [2]
Resistant Disease Human immunodeficiency virus infection [ICD-11: 1C62.0]
 Disease Info 
Molecule Alteration Mutation
A2064C
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model DS9 cells N.A. Homo sapiens (Human) N.A.
LTNP5 cells N.A. Homo sapiens (Human) N.A.
SM-1 cells N.A. Homo sapiens (Human) CVCL_IU19
SM2 cells N.A. Homo sapiens (Human) N.A.
CM-9 cells N.A. Homo sapiens (Human) CVCL_Y624
DU151 cells Prostate Homo sapiens (Human) N.A.
DU178 cells Prostate Homo sapiens (Human) N.A.
DU422 cells Prostate Homo sapiens (Human) N.A.
Experiment for
Drug Resistance		 In vitro phenotypic DOR susceptibility testing
Mechanism Description This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y191L caused high-level resistance, in agreement with the predictions.
Key Molecule: Reverse transcriptase (RT) [2]
Resistant Disease Human immunodeficiency virus infection [ICD-11: 1C62.0]
 Disease Info 
Molecule Alteration Mutation
K344R
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model DS9 cells N.A. Homo sapiens (Human) N.A.
LTNP5 cells N.A. Homo sapiens (Human) N.A.
SM-1 cells N.A. Homo sapiens (Human) CVCL_IU19
SM2 cells N.A. Homo sapiens (Human) N.A.
CM-9 cells N.A. Homo sapiens (Human) CVCL_Y624
DU151 cells Prostate Homo sapiens (Human) N.A.
DU178 cells Prostate Homo sapiens (Human) N.A.
DU422 cells Prostate Homo sapiens (Human) N.A.
Experiment for
Drug Resistance		 In vitro phenotypic DOR susceptibility testing
Mechanism Description This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y193L caused high-level resistance, in agreement with the predictions.
Key Molecule: Reverse transcriptase (RT) [2]
Resistant Disease Human immunodeficiency virus infection [ICD-11: 1C62.0]
 Disease Info 
Molecule Alteration Mutation
L2003M
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model DS9 cells N.A. Homo sapiens (Human) N.A.
LTNP5 cells N.A. Homo sapiens (Human) N.A.
SM-1 cells N.A. Homo sapiens (Human) CVCL_IU19
SM2 cells N.A. Homo sapiens (Human) N.A.
CM-9 cells N.A. Homo sapiens (Human) CVCL_Y624
DU151 cells Prostate Homo sapiens (Human) N.A.
DU178 cells Prostate Homo sapiens (Human) N.A.
DU422 cells Prostate Homo sapiens (Human) N.A.
Experiment for
Drug Resistance		 In vitro phenotypic DOR susceptibility testing
Mechanism Description This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y192L caused high-level resistance, in agreement with the predictions.
Key Molecule: Reverse transcriptase (RT) [2]
Resistant Disease Human immunodeficiency virus infection [ICD-11: 1C62.0]
 Disease Info 
Molecule Alteration Mutation
V106M
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model DS9 cells N.A. Homo sapiens (Human) N.A.
LTNP5 cells N.A. Homo sapiens (Human) N.A.
SM-1 cells N.A. Homo sapiens (Human) CVCL_IU19
SM2 cells N.A. Homo sapiens (Human) N.A.
CM-9 cells N.A. Homo sapiens (Human) CVCL_Y624
DU151 cells Prostate Homo sapiens (Human) N.A.
DU178 cells Prostate Homo sapiens (Human) N.A.
DU422 cells Prostate Homo sapiens (Human) N.A.
Experiment for
Drug Resistance		 In vitro phenotypic DOR susceptibility testing
Mechanism Description This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions.
Key Molecule: Reverse transcriptase (RT) [2]
Resistant Disease Human immunodeficiency virus infection [ICD-11: 1C62.0]
 Disease Info 
Molecule Alteration Mutation
Y188L
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model DS9 cells N.A. Homo sapiens (Human) N.A.
LTNP5 cells N.A. Homo sapiens (Human) N.A.
SM-1 cells N.A. Homo sapiens (Human) CVCL_IU19
SM2 cells N.A. Homo sapiens (Human) N.A.
CM-9 cells N.A. Homo sapiens (Human) CVCL_Y624
DU151 cells Prostate Homo sapiens (Human) N.A.
DU178 cells Prostate Homo sapiens (Human) N.A.
DU422 cells Prostate Homo sapiens (Human) N.A.
Experiment for
Drug Resistance		 In vitro phenotypic DOR susceptibility testing
Mechanism Description This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y189L caused high-level resistance, in agreement with the predictions.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Reverse transcriptase (RT) [2]
Sensitive Disease Human immunodeficiency virus infection [ICD-11: 1C62.0]
 Disease Info 
Molecule Alteration Mutation
F227L
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model DS9 cells N.A. Homo sapiens (Human) N.A.
LTNP5 cells N.A. Homo sapiens (Human) N.A.
SM-1 cells N.A. Homo sapiens (Human) CVCL_IU19
SM2 cells N.A. Homo sapiens (Human) N.A.
CM-9 cells N.A. Homo sapiens (Human) CVCL_Y624
DU151 cells Prostate Homo sapiens (Human) N.A.
DU178 cells Prostate Homo sapiens (Human) N.A.
DU422 cells Prostate Homo sapiens (Human) N.A.
Experiment for
Drug Resistance		 In vitro phenotypic DOR susceptibility testing
Mechanism Description This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y190L caused high-level resistance, in agreement with the predictions.
References
Ref 1 In vitro resistance selection with doravirine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with distinct mutation development pathways .Antimicrob Agents Chemother. 2015 Jan;59(1):590-8. doi: 10.1128/AAC.04201-14. Epub 2014 Nov 10. 10.1128/AAC.04201-14
Ref 2 K103N, V106M and Y188L Significantly Reduce HIV-1 Subtype C Phenotypic Susceptibility to Doravirine. Viruses. 2024 Sep 20;16(9):1493.

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