- Fragment-Based Discovery of Small Molecules Bound to T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3)
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T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3; HAVCR2) has emerged as an attractive immune checkpoint target for cancer immunotherapy. TIM-3 is a negative regulator of the systemic immune response to cancer and is expressed on several dysfunctional, or exhausted, immune cell subsets. Upregulation of TIM-3 is associated with tumor progression, poor survival rates, and acquired resistance to antibody-based immunotherapies in the clinic. Despite the potential advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has lagged behind that of antibody therapeutics. Here, we describe the discovery of high-affinity small-molecule ligands for TIM-3 through an NMR-based fragment screen and structure-based lead optimization. These compounds represent useful tools to further study the biology of TIM-3 immune modulation in cancer and serve as a potentially useful starting point toward the discovery of TIM-3-targeted therapeutics.
- Rietz, Tyson A.,Teuscher, Kevin B.,Mills, Jonathan J.,Gogliotti, Rocco D.,Lepovitz, Lance T.,Scaggs, W. Rush,Yoshida, Keisuke,Luong, Kelvin,Lee, Taekyu,Fesik, Stephen W.
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p. 14757 - 14772
(2021/10/20)
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- NOVEL ESTROGEN RECEPTOR LIGANDS
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Compounds of formula (I) or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a salt of such an ester, amide or carbamate in which R1 to R9 have meanings as defined in the Specification, are useful as e
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Paragraph 0126
(2014/11/11)
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- NOVEL ESTROGEN RECEPTOR LIGANDS
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Compounds of formula (I) or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a salt of such an ester, amide or carbamate in which R1 to R9 have meanings as defined in the Specification, are useful as estrogen receptor ligands.
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Page/Page column 31
(2013/03/26)
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- Synthesis of Fused Tetrazole Derivatives via a Tandem Cycloaddition and N-Allylation Reaction and Parallel Synthesis of Fused Tetrazole Amines
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A method for the synthesis of novel fused tricyclic tetrazoles from allylic bromides generated by the recently discovered DiazAll reaction has been developed. This new tandem reaction comprises a cycloaddition between a nitrile and (TMS)N3 followed by an intramolecular N-allylation. The variation of functionalities in the benzene moiety was well-tolerated, and only a moderate difference in yield and degree of purity was noticed. An exo-methylene group in these new compounds permitted further derivatization. Structural resemblance with substances which possess important pharmacological properties motivated the synthesis of a series of ketones and a small library of amines.
- Ek, Fredrik,Manner, Sophie,Wistrand, Lars-Goeran,Frejd, Torbjoern
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p. 1346 - 1352
(2007/10/03)
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