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Technical details about Subasumstat, learn more about the structure, uses, toxicity, action, side effects and more

Subasumstat

Synopsis, Chemistry

Subasumstat
Chemistry
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1. Also known as: Tak-981, 1858276-04-6, Subasumstat [usan], Xq43h3v6m1, Sumoylation inhibitor tak-981, [(1r,2s,4r)-4-[[5-[[4-((1r)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methylthien-2-yl]carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate

Molecular Formula

C₂₅H₂₈ClN₅O₅S₂

Molecular Weight

578.1 g/mol

InChI Key

LXRZVMYMQHNYJB-UNXOBOICSA-N

FDA UNII

XQ43H3V6M1

Subasumstat is a small molecule inhibitor of sumoylation, with potential immune-activating and antineoplastic activities. Upon intravenous administration, subasumstat targets and covalently binds to the small ubiquitin-like modifier (SUMO; small ubiquitin-related modifier) protein, forming an adduct with SUMO protein (subasumstat-SUMO adduct). This prevents the transfer of SUMO from the SUMO-activating enzyme (SAE) to SUMO-conjugating enzyme UBC9. This prevents SUMO conjugation to lysine residues on target proteins and abrogates many sumoylated protein-mediated cellular processes that play key roles in tumor cells, including proliferation, DNA repair, metastasis and survival. In addition, by preventing sumoylation, subasumstat is able to increase the production of type 1 interferon (IFN), thereby increasing type 1 IFN-mediated signaling, activating innate effector cells and enhancing the antitumor innate immune responses. This may further increase tumor cell killing. Sumoylation, a post-translational modification that attaches the SUMO protein to target proteins, plays a key role in regulating their activity, function, subcellular localization and stability. Sumoylation also plays a key role in inhibiting innate immune responses, specifically by inhibiting the pattern recognition receptor (PRR) pathway and preventing type 1 IFN expression. Abnormal sumoylation of target proteins is associated with many cancers.

1 2D Structure

2D Structure

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

[(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate

2.1.2 InChI

InChI=1S/C25H28ClN5O5S2/c1-13-18(23-19-7-16(26)3-2-14(19)4-5-29-23)9-22(37-13)24(33)20-10-28-12-30-25(20)31-17-6-15(21(32)8-17)11-36-38(27,34)35/h2-3,7,9-10,12,15,17,21,23,29,32H,4-6,8,11H2,1H3,(H2,27,34,35)(H,28,30,31)/t15-,17-,21+,23+/m1/s1

2.1.3 InChI Key

LXRZVMYMQHNYJB-UNXOBOICSA-N

2.1.4 Canonical SMILES

CC1=C(C=C(S1)C(=O)C2=CN=CN=C2NC3CC(C(C3)O)COS(=O)(=O)N)C4C5=C(CCN4)C=CC(=C5)Cl

2.1.5 Isomeric SMILES

CC1=C(C=C(S1)C(=O)C2=CN=CN=C2N[C@@H]3C[C@@H]([C@H](C3)O)COS(=O)(=O)N)[C@H]4C5=C(CCN4)C=CC(=C5)Cl

2.2 Other Identifiers

2.2.1 UNII

XQ43H3V6M1

2.3 Synonyms

2.3.1 Depositor-Supplied Synonyms

1. Tak-981

2. 1858276-04-6

3. Subasumstat [usan]

4. Xq43h3v6m1

5. Sumoylation Inhibitor Tak-981

6. [(1r,2s,4r)-4-[[5-[[4-((1r)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methylthien-2-yl]carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl Sulfamate

7. 1858276-04-6 (free)

8. ((1r,2s,4r)-4-((5-(4-((r)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methylthiophene-2-carbonyl)pyrimidin-4-yl)amino)-2-hydroxycyclopentyl)methyl Sulfamate

9. ((1r,2s,4r)-4-((5-((4-((1r)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methylthien-2-yl)carbonyl)pyrimidin-4-yl)amino)-2-hydroxycyclopentyl)methyl Sulfamate

10. [(1r,2s,4r)-4-[(5-[4-[(1r)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl)amino]-2-hydroxycyclopentyl]methyl Sulfamate

11. [(1r,2s,4r)-4-[[5-[4-[(1r)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl Sulfamate

12. Tak981 Oxalate

13. Tak-981 Oxalate

14. Subasumstat [inn]

15. Subasumstat (proposed Inn)

16. Unii-xq43h3v6m1

17. Subasumstat [who-dd]

18. Tak981

19. Chembl4862901

20. Schembl17398333

21. Gtpl11305

22. Bdbm462958

23. Tak 981; Tak981

24. Bcp30806

25. Ex-a3291

26. Mfcd32062692

27. Nsc820784

28. Who 11858

29. Nsc-820784

30. Us10780090, Compound I-263a

31. Us10780090, Compound I-263b

32. Ac-35773

33. Example 133 [wo2016004136a1]

34. Hy-111789

35. Cs-0091878

36. D81004

37. A935089

38. I-263a [wo2016004136a1]

39. [(1r,2s,4r)-4-[[5-[4-[(1r)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-thiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxy-cyclopentyl]methyl Sulfamate

40. [(1r,2s,4r)-4-{[5-({4-[(1r)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2- Thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl Sulfamate

41. Sulfamic Acid, ((1r,2s,4r)-4-((5-((4-((1r)-7-chloro-1,2,3,4-tetrahydro-1-isoquinolinyl)-5-methyl-2-thienyl)carbonyl)-4-pyrimidinyl)amino)-2-hydroxycyclopentyl)methyl Ester

2.4 Create Date

2016-02-23

3 Chemical and Physical Properties

Molecular Formula	C₂₅H₂₈ClN₅O₅S₂
Molecular Weight	578.1 g/mol
XLogP3	3.5
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	8
Exact Mass	577.1220391 g/mol
Monoisotopic Mass	577.1220391 g/mol
Topological Polar Surface Area	193 Å²
Heavy Atom Count	38
Formal Charge	0
Complexity	942
Isotope Atom Count	0
Defined Atom Stereocenter Count	4
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Pharmacology and Biochemistry

4.1 Mechanism of Action

Subasumstat binds and forms an adduct with SUMO, stopping the protein from transferring from the SUMO-activating enzyme to SUMO-conjugating enzyme UBC9. Downstream, this stops many sumoylated protein-mediated pathways from occurring in tumor cells, like DNA repair, metastasis, and proliferation. Subasumstat is also able to increase the production of type 1 interferon, which activates antitumor immune responses in cells and signals for increased tumor cell death.

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