Sotorasib

Identification

Summary

Sotorasib is an experimental KRAS inhibitor being investigated for the treatment of KRAS G12C mutant non small cell lung cancer, colorectal cancer, and appendix cancer.

Brand Names
Lumakras
Generic Name
Sotorasib
DrugBank Accession Number
DB15569
Background

Sotorasib, also known as AMG-510, is an acrylamide derived KRAS inhibitor developed by Amgen.1,3 It is indicated in the treatment of adult patients with KRAS G12C mutant non small cell lung cancer.6 This mutation makes up >50% of all KRAS mutations.2 Mutant KRAS discovered in 1982 but was not considered a druggable target until the mid-2010s.5 It is the first experimental KRAS inhibitor.1

The drug MRTX849 is also currently being developed and has the same target.1

Sotorasib was granted FDA approval on 28 May 2021.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 560.606
Monoisotopic: 560.234745176
Chemical Formula
C30H30F2N6O3
Synonyms
  • Kras G12C inhibitor 9
  • Sotorasib
External IDs
  • AMG 510
  • AMG-510
  • AMG510

Pharmacology

Indication

Sotorasib is indicated in the treatment of adults with KRAS G12C mutant non small cell lung cancer.6

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Sotorasib is indicated in the treatment of adults with KRAS G12C mutant non small cell lung cancer.6 It has a moderate duration of action as it is given daily.6 Patients should be counselled regarding the risks of hepatotoxicity, interstitial lung disease and pneumonitis; and to avoid breastfeeding during treatment and up to 1 week after the last dose.6

Mechanism of action

Normally GTP binds to KRAS, activating the protein and promoting effectors to the MAP kinase pathway.3 GTP is hydrolyzed to GDP, and KRAS is inactivated.4 KRAS G12C mutations impair hydrolysis of GTP, leaving it in the active form.4

Sotorasib binds to the cysteine residue in KRAS G12C mutations, holding the protein in its inactive form.1 The cysteine residue that sotorasib targets is not present in the wild type KRAS, which prevents off-target effects.6 This mutation is present in 13% of non small cell lung cancer, 3% of colorectal and appendix cancer, and 1-3% of solid tumors.1

TargetActionsOrganism
AGTPase KRas
inhibitor
Humans
Absorption

A 960 mg once daily dose of sotorasib reaches a Cmax of 7.50 µg/mL, with a median Tmax of 2.0 hours, and an AUC0-24h of 65.3 h*µg/mL.5

Volume of distribution

The volume of distribution of sotorasib is 211 L.6

Protein binding

Sotorasib is 89% protein bound in plasma.6

Metabolism

Sotorasib is predominantly metabolized through conjugation or by CYP3As.6

Route of elimination

Sotorasib is 74% eliminated in the feces and 6% eliminated in the urine.6 53% of the dose recovered in the feces and 1% of the dose recovered in the urine is in the form of the unchanged parent compound.6

Half-life

Sotorasib has a terminal elimination half life of 5.5 ± 1.8 hours.5,6

Clearance

Sotorasib has an apparent clearance at steady state of 26.2 L/h.6

Adverse Effects
Adverseeffects
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Toxicity

Data regarding overdoses of sotorasib are not readily available. However, in clinical trials, signs of dose limiting toxicity were not found.5 Patients experiencing an overdose may experience and increased risk and severity of adverse effects such as diarrhea, nausea, vomiting, fatigue, and elevated aminotransferase.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe serum concentration of 1,2-Benzodiazepine can be decreased when it is combined with Sotorasib.
AbemaciclibThe serum concentration of Abemaciclib can be decreased when it is combined with Sotorasib.
AbirateroneThe serum concentration of Abiraterone can be decreased when it is combined with Sotorasib.
AcalabrutinibThe serum concentration of Acalabrutinib can be decreased when it is combined with Sotorasib.
AcenocoumarolThe serum concentration of Acenocoumarol can be decreased when it is combined with Sotorasib.
AcetaminophenThe serum concentration of Acetaminophen can be decreased when it is combined with Sotorasib.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Sotorasib.
AlbendazoleThe serum concentration of Albendazole can be decreased when it is combined with Sotorasib.
AlclometasoneThe serum concentration of Alclometasone can be decreased when it is combined with Sotorasib.
AlectinibThe serum concentration of Alectinib can be decreased when it is combined with Sotorasib.
Interactions
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Food Interactions
  • Avoid antacids. If coadministration cannot be avoided, take sotorasib 4 hours before or 10 hours after antacids.
  • Take with or without food. Taking sotorasib with a high fat, high calorie meal increases total exposure to sotorasib by 25%.

Products

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International/Other Brands
Lumakras (Amgen)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LumakrasTablet, coated120 mg/1OralAMGEN INC2021-05-28Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans

Chemical Identifiers

UNII
2B2VM6UC8G
CAS number
2252403-56-6
InChI Key
NXQKSXLFSAEQCZ-SFHVURJKSA-N
InChI
InChI=1S/C30H30F2N6O3/c1-6-23(40)36-12-13-37(18(5)15-36)28-19-14-21(32)26(24-20(31)8-7-9-22(24)39)34-29(19)38(30(41)35-28)27-17(4)10-11-33-25(27)16(2)3/h6-11,14,16,18,39H,1,12-13,15H2,2-5H3/t18-/m0/s1
IUPAC Name
6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-1H,2H-pyrido[2,3-d]pyrimidin-2-one
SMILES
CC(C)C1=NC=CC(C)=C1N1C(=O)N=C(N2CCN(C[C@@H]2C)C(=O)C=C)C2=CC(F)=C(N=C12)C1=C(O)C=CC=C1F

References

General References
  1. Authors unspecified: AMG 510 First to Inhibit "Undruggable" KRAS. Cancer Discov. 2019 Aug;9(8):988-989. doi: 10.1158/2159-8290.CD-NB2019-073. Epub 2019 Jun 12. [Article]
  2. Fiala O, Pesek M, Finek J, Benesova L, Belsanova B, Minarik M: The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Cancer Genet. 2013 Jan-Feb;206(1-2):26-31. doi: 10.1016/j.cancergen.2012.12.003. Epub 2013 Jan 10. [Article]
  3. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O'Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR: The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Oct 30. pii: 10.1038/s41586-019-1694-1. doi: 10.1038/s41586-019-1694-1. [Article]
  4. Christensen JG, Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, Sudhakar N, Bowcut V, Baer BR, Ballard JA, Burkard MR, Fell JB, Fischer JP, Vigers GP, Xue JY, Gatto S, Fernandez-Banet J, Pavlicek A, Velastegui K, Chao RC, Barton J, Pierobon M, Baldelli E, Patricoin EF, Cassidy DP, Marx MA, Rybkin II, Johnson ML, Ou SI, Lito P, Papadopoulos KP, Janne PA, Olson P: The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2019 Oct 28. pii: 2159-8290.CD-19-1167. doi: 10.1158/2159-8290.CD-19-1167. [Article]
  5. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang YJ, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT: KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020 Sep 24;383(13):1207-1217. doi: 10.1056/NEJMoa1917239. Epub 2020 Sep 20. [Article]
  6. FDA Approved Drug Products: Lumakras (Sotorasib) Oral Tablet [Link]
KEGG Drug
D12055
ChemSpider
72380148
BindingDB
50514402
RxNav
2550714
ChEMBL
CHEMBL4535757
Wikipedia
Sotorasib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentKRAS p, G12c Mutated /Advanced Metastatic NSCLC1
2Not Yet RecruitingTreatmentAdenocarcinoma of Lung (Disorder) / Non-Small Cell Lung Carcinoma (NSCLC) / Recurrent Non-Squamous Non-Small Cell Lung Carcinoma / Stage IV Lung Cancer AJCC v8 / Stage IVA Lung Cancer AJCC v8 / Stage IVB Lung Cancer AJCC v81
2Not Yet RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
1Active Not RecruitingTreatmentAdvanced/Metastatic Solid Tumors With KRAS p.G12C Mutation1
1RecruitingBasic ScienceHepatic Impairment1
1, 2RecruitingTreatmentKirsten Rat Sarcoma (KRAS) pG12C Mutation / Solid Tumors, Advanced Solid Tumors1
1, 2RecruitingTreatmentKRAS p.G12C Mutant Advanced Solid Tumors1
Not AvailableAvailableNot AvailableLocally Advanced Metastatic NSCLC / Non-Small Cell Lung Carcinoma (NSCLC) / Unresectable Locally Advanced NSCLC1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, coatedOral120 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility1.3 mg/mL at pH 1.2, 0.03 mg/mL at pH 6.8FDA
pKa8.06, 4.56FDA
Predicted Properties
PropertyValueSource
Water Solubility0.0185 mg/mLALOGPS
logP3.6ALOGPS
logP4.74ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)6.98ChemAxon
pKa (Strongest Basic)4.74ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area102.23 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity150.12 m3·mol-1ChemAxon
Polarizability57.21 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein complex binding
Specific Function
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838).
Gene Name
KRAS
Uniprot ID
P01116
Uniprot Name
GTPase KRas
Molecular Weight
21655.67 Da
References
  1. Authors unspecified: AMG 510 First to Inhibit "Undruggable" KRAS. Cancer Discov. 2019 Aug;9(8):988-989. doi: 10.1158/2159-8290.CD-NB2019-073. Epub 2019 Jun 12. [Article]
  2. Fiala O, Pesek M, Finek J, Benesova L, Belsanova B, Minarik M: The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Cancer Genet. 2013 Jan-Feb;206(1-2):26-31. doi: 10.1016/j.cancergen.2012.12.003. Epub 2013 Jan 10. [Article]
  3. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O'Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR: The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Oct 30. pii: 10.1038/s41586-019-1694-1. doi: 10.1038/s41586-019-1694-1. [Article]
  4. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, Hong CB, Corcoran RB: Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRAS(G12C) Inhibition. Clin Cancer Res. 2020 Apr 1;26(7):1633-1643. doi: 10.1158/1078-0432.CCR-19-3523. Epub 2019 Nov 27. [Article]
  5. Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G, Kopecky DJ, Liu L, Lopez P, Low JD, Ma V, Minatti AE, Nguyen TT, Nishimura N, Pickrell AJ, Reed AB, Shin Y, Siegmund AC, Tamayo NA, Tegley CM, Walton MC, Wang HL, Wurz RP, Xue M, Yang KC, Achanta P, Bartberger MD, Canon J, Hollis LS, McCarter JD, Mohr C, Rex K, Saiki AY, San Miguel T, Volak LP, Wang KH, Whittington DA, Zech SG, Lipford JR, Cee VJ: Discovery of a Covalent Inhibitor of KRAS(G12C) (AMG 510) for the Treatment of Solid Tumors. J Med Chem. 2020 Jan 9;63(1):52-65. doi: 10.1021/acs.jmedchem.9b01180. Epub 2019 Dec 24. [Article]
  6. Madhyastha N, Samantha SK, Dittakavi S, Markose M, Mallurwar SR, Zainuddin M, Mullangi R: Validated HPLC-MS/MS method for quantitation of AMG 510, a KRAS G12C inhibitor, in mouse plasma and its application to a pharmacokinetic study in mice. Biomed Chromatogr. 2021 Apr;35(4):e5043. doi: 10.1002/bmc.5043. Epub 2021 Jan 19. [Article]
  7. Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, Michel AG, Syed MU, Fella KA, Sakhi M, Baiev I, Juric D, Gainor JF, Klempner SJ, Lennerz JK, Siravegna G, Bar-Peled L, Hata AN, Heist RS, Corcoran RB: Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. 2021 Apr 6. pii: 2159-8290.CD-21-0365. doi: 10.1158/2159-8290.CD-21-0365. [Article]

Enzymes

Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. FDA Approved Drug Products: Lumakras (Sotorasib) Oral Tablet [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: Lumakras (Sotorasib) Oral Tablet [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: Lumakras (Sotorasib) Oral Tablet [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: Lumakras (Sotorasib) Oral Tablet [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Lumakras (Sotorasib) Oral Tablet [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Lumakras (Sotorasib) Oral Tablet [Link]

Drug created on November 01, 2019 18:34 / Updated on June 02, 2021 20:05