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Adagrasib

PubChem CID
138611145
Structure
Adagrasib_small.png
Adagrasib_3D_Structure.png
Molecular Formula
Synonyms
  • MRTX849
  • Adagrasib
  • 2326521-71-3
  • MRTX-849
  • KRAZATI
Molecular Weight
604.1 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2019-07-20
  • Modify:
    2025-01-04
Description
Adagrasib (MRTX849) is an oral, small-molecule KRAS inhibitor developed by Mirati Therapeutics. KRAS mutations are highly common in cancer and account for approximately 85% of all RAS family mutations. However, the development of KRAS inhibitors has been challenging due to their high affinity for guanosine triphosphate (GTP) and guanosine diphosphate (GDP), as well as the lack of a clear binding pocket. Adagrasib targets KRASG12C, one of the most common KRAS mutations, at the cysteine 12 residue and inhibits KRAS-dependent signalling. In a phase I/IB clinical study that included patients with KRASG12C-mutated advanced solid tumors (NCT03785249), adagrasib exhibited anti-tumor activity. The phase II of the same study showed that in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC), adagrasib was efficient without new safety signals. In February 2022, the FDA accepted a new drug application (NDA) for adagrasib for the treatment of patients with previously treated KRASG12C–positive NSCLC. In December 2022, the FDA granted accelerated approval to adagrasib for the treatment of KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy. Adagrasib joins [sotorasib] as another KRASG12C inhibitor approved by the FDA.
Adagrasib is a small molecule inhibitor of the KRAS G12C mutant protein which is found in up to 13% of refractory cases of non-small cell lung cancer. Serum aminotransferase elevations are common during therapy with adagrasib, and a proportion of patients develop clinically apparent liver injury that can be severe.
Adagrasib is an orally available, small molecule inhibitor that targets the oncogenic KRAS substitution mutation, G12C, with potential antineoplastic activity. Upon oral administration adagrasib covalently binds to cytosine 12 within the switch II pocket of GDP-bound KRAS G12C, thereby inhibiting mutant KRAS-dependent signaling. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Adagrasib.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C32H35ClFN7O2/c1-21(34)31(42)41-17-16-40(18-23(41)11-13-35)30-25-12-15-39(28-10-4-7-22-6-3-9-26(33)29(22)28)19-27(25)36-32(37-30)43-20-24-8-5-14-38(24)2/h3-4,6-7,9-10,23-24H,1,5,8,11-12,14-20H2,2H3/t23-,24-/m0/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

PEMUGDMSUDYLHU-ZEQRLZLVSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CN1CCC[C@H]1COC2=NC3=C(CCN(C3)C4=CC=CC5=C4C(=CC=C5)Cl)C(=N2)N6CCN([C@H](C6)CC#N)C(=O)C(=C)F
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C32H35ClFN7O2
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2326521-71-3

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEMBL ID

2.3.5 DrugBank ID

2.3.6 DSSTox Substance ID

2.3.7 KEGG ID

2.3.8 NCI Thesaurus Code

2.3.9 PharmGKB ID

2.3.10 Pharos Ligand ID

2.3.11 RXCUI

2.3.12 Wikidata

2.3.13 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido(3,4-d)pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
  • 2-Piperazineacetonitrile, 4-(7-(8-chloro-1-naphthalenyl)-5,6,7,8-tetrahydro-2-(((2S)-1-methyl-2-pyrrolidinyl)methoxy)pyrido(3,4-d)pyrimidin-4-yl)-1-(2-fluoro-1-oxo-2-propen-1-yl)-, (2S)-
  • adagrasib
  • MRTX-849
  • MRTX849

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
604.1 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
5
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
9
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
603.2524792 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
603.2524792 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
88.8 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
43
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1060
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Melting Point

From > 262 mg/mL to < 0.010 mg/mL
FDA label

3.3 Chemical Classes

3.3.1 Drugs

3.3.1.1 Human Drugs
Human drug -> Active ingredient (ADAGRASIB)
Human drug -> Prescription
Paediatric drug

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

Adagrasib is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).
Treatment of all solid and haematological malignancies

6.2 LiverTox Summary

Adagrasib is a small molecule inhibitor of the KRAS G12C mutant protein which is found in up to 13% of refractory cases of non-small cell lung cancer. Serum aminotransferase elevations are common during therapy with adagrasib, and a proportion of patients develop clinically apparent liver injury that can be severe.

6.3 Drug Classes

Antineoplastic Agents

6.4 FDA Approved Drugs

6.5 FDA Orange Book

6.6 FDA National Drug Code Directory

6.7 Drug Labels

Drug and label
Active ingredient and drug

6.8 Cancer Drugs

Drug Name
Adagrasib
Brand Name(s)
Krazati
FDA Approved
Yes
Drug Use

Adagrasib is approved to treat adults with cancer that has spread and has an abnormal KRAS gene, including:

• non-small cell lung cancer (NSCLC). It is used in patients who have received at least one other systemic therapy

• colorectal cancer. It is used with cetuximab in patients who have received chemotherapy that included a fluoropyrimidine, oxaliplatin, and irinotecan hydrochloride

These uses are approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that adagrasib provides a clinical benefit in these patients.Adagrasib is also being studied in the treatment of other types of cancer.

6.9 Clinical Trials

6.9.1 ClinicalTrials.gov

6.9.2 EU Clinical Trials Register

6.10 EMA Drug Information

Type
Paediatric investigation
Active Substance
Therapeutic Area
Oncology
Drug Form
Tablet, Capsule, hard
Administration Route
Oral use
Decision Type
W: decision granting a waiver in all age groups for all conditions or indications
Decision Date
2021-12-03

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

The exposure-response relationship and pharmacodynamic response time course of adagrasib have not been elucidated. The use of adagrasib can cause QTc interval prolongation. The increase in QTc is concentration-dependent. In patients given 600 mg of adagrasib twice daily, the mean QTcF change from baseline (ΔQTcF) was 18 ms at the mean steady-state maximum concentration. The use of adagrasib can also lead to severe gastrointestinal adverse reactions, hepatotoxicity and interstitial lung disease/pneumonitis.

7.2 MeSH Pharmacological Classification

Antineoplastic Agents
Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

7.3 ATC Code

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01X - Other antineoplastic agents

L01XX - Other antineoplastic agents

L01XX77 - Adagrasib

7.4 Absorption, Distribution and Excretion

Absorption
The AUC and Cmax of adagrasib increase in a dose-proportional manner between 400 mg and 600 mg (0.67 to 1 times the approved recommended dose). At the recommended dose, adagrasib reached steady-state within 8 days, with a 6-fold accumulation. The Tmax of adagrasib is approximately 6 hours. The administration of a high-fat and high-calorie meal (900-1000 calories, 50% from fat) did not have a clinically significant effect on the pharmacokinetics of adagrasib. Adagrasib has high oral bioavailability and is able to penetrate the central nervous system.
Route of Elimination
Adagrasib is eliminated through feces and urine. In patients given a single dose of radiolabeled adagrasib, 75% of the dose was recovered in feces (14% as unchanged), while 4.5% was recovered in urine (2% as unchanged).
Volume of Distribution
Adagrasib has an apparent volume of distribution of 942 L.
Clearance
Adagrasib has an apparent oral clearance (CL/F) of 37 L/h.

7.5 Metabolism / Metabolites

Following single-dose administration, adagrasib is mainly metabolized by CYP3A4. However, since adagrasib inhibits CYP3A4 following multiple dosing, other enzymes such as CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 contribute to its metabolism at steady-state.

7.6 Biological Half-Life

Adagrasib has a terminal elimination half-life of 23 hours.

7.7 Mechanism of Action

In normal cells, KRAS is activated by binding to guanosine triphosphate (GTP), and this promotes the activation of the MAP kinase pathway and intracellular signal transduction. When GTP is hydrolyzed to guanosine diphosphate (GDP), KRAS is inactivated. This mechanism works as an "on"/"off" system that regulates cell growth. The substitution of Gly12 by cysteine in KRAS (KRASG12C) impairs GTP hydrolysis, and maintains KRAS in its active form. Therefore, the presence of this mutation leads to uncontrolled cellular proliferation and growth, as well as malignant transformation. Adagrasib is a covalent inhibitor of KRASG12C that irreversibly and selectively binds and locks KRASG12C in its inactive, guanosine diphosphate–bound state. Therefore, the use of adagrasib inhibits tumor cell growth and viability in cancers with KRASG12C mutations with minimal off-target activity.

8 Use and Manufacturing

8.1 Uses

8.1.1 Use Classification

Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9 Safety and Hazards

9.1 Hazards Identification

9.1.1 GHS Classification

Note
Pictograms displayed are for 66.7% (2 of 3) of reports that indicate hazard statements. This chemical does not meet GHS hazard criteria for 33.3% (1 of 3) of reports.
Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements

H302 (66.7%): Harmful if swallowed [Warning Acute toxicity, oral]

H315 (66.7%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (66.7%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (66.7%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Precautionary Statement Codes

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria per 1 of 3 reports by companies. For more detailed information, please visit ECHA C&L website.

There is 1 notification provided by 2 of 3 reports by companies with hazard statement code(s).

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

9.1.2 Hazard Classes and Categories

Acute Tox. 4 (66.7%)

Skin Irrit. 2 (66.7%)

Eye Irrit. 2A (66.7%)

STOT SE 3 (66.7%)

10 Toxicity

10.1 Toxicological Information

10.1.1 Hepatotoxicity

In the prelicensure clinical trials of adagrasib in patients with solid tumors harboring KRAS G12C mutations, liver test abnormalities were frequent although usually self-limited and mild. Some degree of ALT elevations arose in 28% to 46% of adagrasib treated patients and elevations above 5 times the upper limit of normal (ULN) were seen in 5% to 7%. In these trials that enrolled approximately 366 patients, adagrasib was discontinued early due to increased AST or ALT in 8% of patients. In addition, a small proportion of patients developed clinically apparent hepatotoxicity requiring adagrasib discontinuation. The liver test abnormalities had a median onset of 3 weeks after initiation of therapy. While serum aminotransferase elevations were occasionally quite high (5 to 20 times ULN), there were no accompanying elevations in serum bilirubin and no patient developed clinically apparent liver injury with jaundice. The product label for adagrasib recommends monitoring for routine liver tests before, at 3 week intervals during the first 3 months of therapy, and thereafter as clinically indicated.

Likelihood score: D (possible but infrequent cause of clinically apparent liver injury).

10.1.2 Protein Binding

_In vitro_, adagrasib has a human plasma protein binding of 98%.

11 Associated Disorders and Diseases

12 Literature

12.1 Consolidated References

12.2 NLM Curated PubMed Citations

12.3 Thieme References

12.4 Nature Journal References

12.5 Chemical Co-Occurrences in Literature

12.6 Chemical-Gene Co-Occurrences in Literature

12.7 Chemical-Disease Co-Occurrences in Literature

13 Patents

13.1 Depositor-Supplied Patent Identifiers

13.2 WIPO PATENTSCOPE

13.3 FDA Orange Book Patents

14 Interactions and Pathways

14.1 Chemical-Target Interactions

14.2 Drug-Drug Interactions

15 Biological Test Results

15.1 BioAssay Results

16 Classification

16.1 MeSH Tree

16.2 NCI Thesaurus Tree

16.3 KEGG: USP

16.4 KEGG: ATC

16.5 KEGG: Target-based Classification of Drugs

16.6 KEGG: Drug Groups

16.7 WHO ATC Classification System

16.8 ChemIDplus

16.9 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

16.10 ChEMBL Target Tree

16.11 UN GHS Classification

16.12 EPA DSSTox Classification

16.13 PFAS and Fluorinated Organic Compounds in PubChem

16.14 MolGenie Organic Chemistry Ontology

17 Information Sources

  1. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  2. Chemical Probes Portal
  3. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  4. IUPHAR/BPS Guide to PHARMACOLOGY
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    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  5. Therapeutic Target Database (TTD)
  6. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  7. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  8. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  9. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
    https://echa.europa.eu/substance-information/-/substanceinfo/100.329.928
    2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (EC: 870-640-0)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/318082
  10. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  11. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  12. DailyMed
  13. LiverTox
  14. NCI Thesaurus (NCIt)
    LICENSE
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    https://www.cancer.gov/policies/copyright-reuse
  15. Open Targets
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    https://platform-docs.opentargets.org/licence
  16. European Medicines Agency (EMA)
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    https://www.ema.europa.eu/en/about-us/legal-notice
  17. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  18. EU Clinical Trials Register
  19. FDA Orange Book
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  20. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  21. National Drug Code (NDC) Directory
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  22. Nature Chemical Biology
  23. NCI Cancer Drugs
  24. NLM RxNorm Terminology
    LICENSE
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  25. PharmGKB
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    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  26. Pharos
    LICENSE
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    https://pharos.nih.gov/about
    2-((S)-4-(7-(8-Chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
    https://pharos.nih.gov/ligands/J66TKZAG9PRG
  27. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  28. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    https://www.whocc.no/copyright_disclaimer/
  29. Wikidata
  30. Wikipedia
  31. PubChem
  32. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
  33. GHS Classification (UNECE)
  34. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  35. PATENTSCOPE (WIPO)
CONTENTS