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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Sotorasib (DB15569)

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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

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Associated Conditions

• Locally Advanced Non-Small Cell Lung Cancer
• Metastatic Non-Small Cell Lung Cancer

Contraindications & Blackbox Warnings

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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

Target	Actions	Organism
AGTPase KRas	inhibitor	Humans

Absorption

A 960 mg once daily dose of sotorasib reaches a C_max of 7.50 µg/mL, with a median T_max of 2.0 hours, and an AUC_0-24h 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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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1,2-Benzodiazepine	The serum concentration of 1,2-Benzodiazepine can be decreased when it is combined with Sotorasib.
Abemaciclib	The serum concentration of Abemaciclib can be decreased when it is combined with Sotorasib.
Abiraterone	The serum concentration of Abiraterone can be decreased when it is combined with Sotorasib.
Acalabrutinib	The serum concentration of Acalabrutinib can be decreased when it is combined with Sotorasib.
Acenocoumarol	The serum concentration of Acenocoumarol can be decreased when it is combined with Sotorasib.
Acetaminophen	The serum concentration of Acetaminophen can be decreased when it is combined with Sotorasib.
Afatinib	The serum concentration of Afatinib can be increased when it is combined with Sotorasib.
Albendazole	The serum concentration of Albendazole can be decreased when it is combined with Sotorasib.
Alclometasone	The serum concentration of Alclometasone can be decreased when it is combined with Sotorasib.
Alectinib	The serum concentration of Alectinib can be decreased when it is combined with Sotorasib.

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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%.

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International/Other Brands

Lumakras (Amgen)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Lumakras	Tablet, coated	120 mg/1	Oral	AMGEN INC	2021-05-28	Not applicable

Categories

Drug Categories

• Antineoplastic Agents
• BCRP/ABCG2 Inhibitors
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (strength unknown)
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (strength unknown)
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Substrates
• P-glycoprotein inhibitors

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]

External Links

KEGG Drug

D12055

ChemSpider

72380148

BindingDB

50514402

RxNav

2550714

ChEMBL

CHEMBL4535757

Wikipedia

Sotorasib

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	KRAS p, G12c Mutated /Advanced Metastatic NSCLC	1
2	Not Yet Recruiting	Treatment	Adenocarcinoma 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 v8	1
2	Not Yet Recruiting	Treatment	Non-Small Cell Lung Carcinoma (NSCLC)	1
1	Active Not Recruiting	Treatment	Advanced/Metastatic Solid Tumors With KRAS p.G12C Mutation	1
1	Recruiting	Basic Science	Hepatic Impairment	1
1, 2	Recruiting	Treatment	Kirsten Rat Sarcoma (KRAS) pG12C Mutation / Solid Tumors, Advanced Solid Tumors	1
1, 2	Recruiting	Treatment	KRAS p.G12C Mutant Advanced Solid Tumors	1
Not Available	Available	Not Available	Locally Advanced Metastatic NSCLC / Non-Small Cell Lung Carcinoma (NSCLC) / Unresectable Locally Advanced NSCLC	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, coated	Oral	120 mg/1

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	1.3 mg/mL at pH 1.2, 0.03 mg/mL at pH 6.8	FDA
pKa	8.06, 4.56	FDA

Predicted Properties

Property	Value	Source
Water Solubility	0.0185 mg/mL	ALOGPS
logP	3.6	ALOGPS
logP	4.74	ChemAxon
logS	-4.5	ALOGPS
pKa (Strongest Acidic)	6.98	ChemAxon
pKa (Strongest Basic)	4.74	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	7	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	102.23 Å2	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	150.12 m3·mol-1	ChemAxon
Polarizability	57.21 Å3	ChemAxon
Number of Rings	5	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. GTPase KRas

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]

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