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Sacituzumab Govitecan

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Chemistry

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Also known as: Sacituzumab govitecan [usan], 1491917-83-9, Hrs7-sn38, Unii-m9byu8xdq6, Hrs 7sn38, Immu 132

Molecular Formula

C₇₆H₁₀₄N₁₂O₂₄S

Molecular Weight

1601.8 g/mol

InChI Key

ULRUOUDIQPERIJ-PQURJYPBSA-N

FDA UNII

DA64T2C2IO

Sacituzumab Govitecan is an antibody drug conjugate containing the humanized monoclonal antibody, hRS7, against tumor-associated calcium signal transducer 2 (TACSTD2 or TROP2) and linked to the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), with potential antineoplastic activity. The antibody moiety of sacituzumab govitecan selectively binds to TROP2. After internalization and proteolytic cleavage, SN-38 selectively stabilizes topoisomerase I-DNA covalent complexes, resulting in DNA breaks that inhibit DNA replication and trigger apoptosis. TROP2, also known as epithelial glycoprotein-1 (EGP-1), is a transmembrane calcium signal transducer that is overexpressed by a variety of human epithelial carcinomas; this antigen is involved in the regulation of cell-cell adhesion and its expression is associated with increased cancer growth, aggressiveness and metastasis.

1 2D Structure

Sacituzumab Govitecan

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(2R)-2-amino-3-[1-[[4-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[2-[[(2S)-6-amino-1-[4-[[(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl]oxycarbonyloxymethyl]anilino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylcarbamoyl]cyclohexyl]methyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid

2.1.2 InChI

InChI=1S/C76H104N12O24S/c1-3-55-56-37-54(89)16-17-61(56)83-68-57(55)43-87-63(68)38-59-58(71(87)95)45-110-74(99)76(59,4-2)112-75(100)111-44-50-10-14-52(15-11-50)81-70(94)62(7-5-6-18-77)82-66(91)47-109-46-65(90)79-19-21-101-23-25-103-27-29-105-31-33-107-35-36-108-34-32-106-30-28-104-26-24-102-22-20-86-42-53(84-85-86)40-80-69(93)51-12-8-49(9-13-51)41-88-67(92)39-64(72(88)96)113-48-60(78)73(97)98/h10-11,14-17,37-38,42,49,51,60,62,64,89H,3-9,12-13,18-36,39-41,43-48,77-78H2,1-2H3,(H,79,90)(H,80,93)(H,81,94)(H,82,91)(H,97,98)/t49?,51?,60-,62-,64?,76-/m0/s1

2.1.3 InChI Key

ULRUOUDIQPERIJ-PQURJYPBSA-N

2.1.4 Canonical SMILES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)OC(=O)OCC5=CC=C(C=C5)NC(=O)C(CCCCN)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN6C=C(N=N6)CNC(=O)C7CCC(CC7)CN8C(=O)CC(C8=O)SCC(C(=O)O)N)C2=NC9=C1C=C(C=C9)O

2.1.5 Isomeric SMILES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)[C@@]4(CC)OC(=O)OCC5=CC=C(C=C5)NC(=O)[C@H](CCCCN)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN6C=C(N=N6)CNC(=O)C7CCC(CC7)CN8C(=O)CC(C8=O)SC[C@@H](C(=O)O)N)C2=NC9=C1C=C(C=C9)O

2.2 Other Identifiers

2.2.1 UNII

DA64T2C2IO

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Hrs7-sn38

2. Immu-132

2.3.2 Depositor-Supplied Synonyms

1. Sacituzumab Govitecan [usan]

2. 1491917-83-9

3. Hrs7-sn38

4. Unii-m9byu8xdq6

5. Hrs 7sn38

6. Immu 132

7. Immu-132

8. Satralizumab Linker

9. Sacituzumab-govitecan

10. M9byu8xdq6

11. Da64t2c2io

12. Cysteinyl Cl2a-sn-38

13. Sn-38 Cysteinyl Conjugate

14. Dtxsid401335985

15. Ex-a4354

16. Govitecan Cysteinyl Conjugate

2.4 Create Date

2015-04-18

3 Chemical and Physical Properties

Molecular Formula	C₇₆H₁₀₄N₁₂O₂₄S
Molecular Weight	1601.8 g/mol
XLogP3	-3.3
Hydrogen Bond Donor Count	8
Hydrogen Bond Acceptor Count	30
Rotatable Bond Count	54
Exact Mass	1600.70071340 g/mol
Monoisotopic Mass	1600.70071340 g/mol
Topological Polar Surface Area	498 Å²
Heavy Atom Count	113
Formal Charge	0
Complexity	3150
Isotope Atom Count	0
Defined Atom Stereocenter Count	3
Undefined Atom Stereocenter Count	1
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Sacituzumab govitecan is indicated for adult patients with metastatic triple-negative breast cancer (mTNBC) who have undergone two or more prior therapies for metastatic disease. Sacituzumab govitecan is also indicated for the treatment of locally advanced or metastatic urothelial cancer in adult patients who have received previous platinum-based therapy and either a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication has been approved under accelerated approval, and continued approval may be contingent on the demonstration of clinical benefit in confirmatory trials.

FDA Label

Treatment of breast cancer

Treatment of urothelial carcinoma

Trodelvy as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, including at least one of them for advanced disease.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Sacituzumab govitecan is a humanized monoclonal antibody/topoisomerase inhibitor conjugate designed to induce DNA damage-mediated cell death preferentially in TROP-2-expressing cancer cells. Detailed pharmacodynamic studies have not been performed for sacituzumab govitecan, although as a therapeutic protein, there is potential for immunogenicity. In addition, sacituzumab govitecan has the potential to cause severe hypersensitivity, nausea and vomiting, and embryo-fetal toxicity. Patients who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia.

5.2 ATC Code

L01XC

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01F - Monoclonal antibodies and antibody drug conjugates

L01FX - Other monoclonal antibodies and antibody drug conjugates

L01FX17 - Sacituzumab govitecan

5.3 Absorption, Distribution and Excretion

Absorption

In patients receiving 10 mg/kg sacituzumab govitecan the C_max of the conjugate was 243,000 45,600 ng/mL while the C_max of free SN-38 was 127 60 ng/mL. Similarly, the AUC_0-168 for the conjugate/free SN-38 was 5,210,000 1,230,000 and 3,900 1,830 ng\*h/mL, respectively.

Route of Elimination

No detailed information exists for sacituzumab govitecan elimination; renal elimination of SN-38 is known to be minimal, and it is expected that the fecal route will be the major contributor.

Volume of Distribution

Sacituzumab govitecan has a mean volume of distribution of 0.045 L/kg.

Clearance

Sacituzumab govitecan has a clearance rate of 0.002 L/h/kg.

5.4 Metabolism/Metabolites

The metabolism of sacituzumab govitecan has not been extensively studied. The SN-38 moiety is known to undergo O-glucuronidation by UGT1A1, presumably in the liver, and the SN-38 glucuronide metabolite SN-38G is found in the serum of patients undergoing treatment.

5.5 Biological Half-Life

Sacituzumab govitecan has a mean half-life of 16 hours, while free SN-38 has a mean half-life of 18 hours.

5.6 Mechanism of Action

Sacituzumab govitecan is an antibody-drug conjugate (ADC) targeting TROP-2-expressing cancer cells to induce DNA-damage-mediated cell death. The conjugate comprises a humanized anti-TROP-2 monoclonal antibody (RS7-3G11, also known as RS7) chemically linked by a hydrolyzable CL2A linker to the cytotoxic drug SN-38. The proposed mechanism of action first involves the binding of the RS7 component to TROP-2, which is highly expressed on the cell surface of multiple cancers. Binding of RS7 to TROP-2 results in rapid internalization of bound antibody, and the likely intracellular release of SN-38 via hydrolysis of the CL2A linker. SN-38 is an active metabolite of the anti-cancer drug [irinotecan], which is thought to work primarily through inhibition of DNA topoisomerase I, leading to DNA damage and eventual cell death. In addition, recent work has identified a possible secondary mechanism of action for SN-38 by disrupting the binding of Far Upstream Binding Protein 1 (FUBP1) to the _FUSE_ elements regulating oncogene expression. In addition to SN-38-mediated cell death, there is also some evidence that the RS7 component of the conjugate drug possesses antibody-directed cellular toxicity.

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