- Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer
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SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.
- Langston, Steven P.,Grossman, Stephen,England, Dylan,Afroze, Roushan,Bence, Neil,Bowman, Douglas,Bump, Nancy,Chau, Ryan,Chuang, Bei-Ching,Claiborne, Christopher,Cohen, Larry,Connolly, Kelly,Duffey, Matthew,Durvasula, Nitya,Freeze, Scott,Gallery, Melissa,Galvin, Katherine,Gaulin, Jeffrey,Gershman, Rachel,Greenspan, Paul,Grieves, Jessica,Guo, Jianping,Gulavita, Nanda,Hailu, Shumet,He, Xingyue,Hoar, Kara,Hu, Yongbo,Hu, Zhigen,Ito, Mitsuhiro,Kim, Mi-Sook,Lane, Scott Weston,Lok, David,Lublinsky, Anya,Mallender, William,McIntyre, Charles,Minissale, James,Mizutani, Hirotake,Mizutani, Miho,Molchinova, Nina,Ono, Koji,Patil, Ashok,Qian, Mark,Riceberg, Jessica,Shindi, Vaishali,Sintchak, Michael D.,Song, Keli,Soucy, Teresa,Wang, Yana,Xu, He,Yang, Xiaofeng,Zawadzka, Agatha,Zhang, Ji,Pulukuri, Sai M.
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p. 2501 - 2520
(2021/04/02)
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- SPIROCYCLIC TETRAHYDROQUINAZOLINES
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Provided are compounds represented by Formula I, wherein R3, A, A1, A2, A3, E, E1, E2, L, Q, Z, and (aa) are as defined in the specification, and the pharmaceutically acceptable salts and solvates thereof. Compounds of Formula (I) are KRAS inhibitors and are thus useful to treat cancer and other diseases.
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Paragraph 0526-0527
(2021/07/17)
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- Spirocyclic tetrahydroquinazolines
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The invention discloses spirocyclic tetrahydroquinazolines , and particularly provide compounds represented by Formula I shown in the specification, and pharmaceutically acceptable salts and solvates thereof. In the formula, R3, A, A1, A2, A3, E, E1, E2, L, Q, Z and a structure shown in the specification are as defined in the specification,. The compounds of formula I are KRAS inhibitors and are therefore useful in the treatment of cancer and other diseases.
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Paragraph 0722; 0725-0727
(2021/07/11)
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- PYRIDINE COMPOUND SUBSTITUTED WITH AZOLE
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The present invention provides a compound represented by formula [I] shown below or a pharmaceutically acceptable salt thereof that has an inhibitory effect on 20-HETE producing enzyme. (in formula [I] above, the structure represented by formula [II] below: represents any of the structures represented by formula group [III] below: R1, R2, R3, and R4 independently represent a hydrogen atom, a fluorine atom, methyl, or the like, R5 represents any of the structures represented by formula group [IV]:
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Paragraph 0966
(2020/07/07)
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- 2-(Bicyclo)alkylamino-derivatives as mediatores of chronic pain and inflammation
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Compounds disclosed herein are bradykinin B1 antagonist compounds useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.
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Page/Page column 19; 28
(2008/06/13)
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- The total synthesis of a technetium chelate - Tamoxifen complex
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A potential agent for imaging breast cancer has been synthesized by derivatization of the anti-estrogen tamoxifen. A multistep synthesis was required to conjugate a technetium chelate to tamoxifen in such a fashion that the biodistribution of the complex should mimic that of the parent compound.
- Bell, Russell A.,Dickson, Kieran C.,Valliant, John F.
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p. 146 - 154
(2007/10/03)
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- Inter- and intramolecular addition/cyclizations of sulfonamide anions with alkynyliodonium triflates. Synthesis of dihydropyrrole, pyrrole, indole, and tosylenamide heterocycles
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The synthesis of dihydropyrroles, pyrroles, and indoles through [3-atom + 2-atom] combination of ethyl or aryl tosylamide anions with phenyl(propynyl)iodonium triflate, and the base-mediated intramolecular bicyclization of alkynyliodonium-bearing tosylamide or tosylimide substrates to furnish bicyclic and tricyclic tosylenamide (-enimide) products, is described. A detailed discussion of the scope, limitations, byproduct formation, and the basis for observed diastereoselectivity is presented.
- Feldman, Ken S.,Bruendl, Michelle M.,Schildknegt, Klaas,Bohnstedt, Adolph C.
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p. 5440 - 5452
(2007/10/03)
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