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1.
Nat Cancer ; 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38565920

RESUMEN

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

2.
J Med Chem ; 66(17): 12203-12224, 2023 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-37669040

RESUMEN

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.


Asunto(s)
Factor XIa , Fibrinolíticos , Anticoagulantes
3.
J Med Chem ; 62(23): 10816-10832, 2019 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-31729873

RESUMEN

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor absorption, distribution, metabolism, and excretion (ADME) properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents toward a polar, water-rich area of the protein. This highly lipophilicity-efficient modification ultimately led to the discovery of compound 14, a potent and selective inhibitor of RORγt with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.


Asunto(s)
Hipersensibilidad Tardía/tratamiento farmacológico , Imidazoles/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Femenino , Transferencia Resonante de Energía de Fluorescencia , Semivida , Imidazoles/química , Imidazoles/farmacocinética , Masculino , Modelos Moleculares , Estructura Molecular , Ratas
4.
Chem Commun (Camb) ; (47): 7327-9, 2009 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-20024217

RESUMEN

A stereoselective gold-catalyzed [2 + 2 + 2] cycloaddition of ketoenynes substituted at the propargylic position with OR groups has been applied for the synthesis of (+)-orientalol F and pubinernoid B.

8.
Chem Commun (Camb) ; (4): 333-46, 2007 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-17220965

RESUMEN

In this feature article we cover most recent efforts in gold-catalysed transformations, highlighting the wide molecular diversity that can be achieved, in particular with regard to the formation of C-C bonds. Mechanistic interpretations of some cyclisations are based on our own work on the skeletal rearrangement of 1,6-enynes.

10.
Chemistry ; 12(23): 5916-23, 2006 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-16755620

RESUMEN

Three pathways actually compete in metal-catalyzed cyclizations of enynes in which the metal selectively activates the alkyne: an endocyclic process and two exo-cyclizations, one proceeding by anti attack of the alkene and a second one resulting in a syn addition. Although cyclobutenes may be formed in transition-metal-catalyzed cyclization of some enynes, particularly, 1,7-enynes, these compounds are not necessarily the intermediates in the skeletal rearrangement. Cyclobutenes are formed by ring expansion of syn-cyclopropyl metal-carbenes formed in the syn pathway.


Asunto(s)
Alquenos/síntesis química , Alquinos/química , Elementos de Transición/química , Alquenos/química , Catálisis , Ciclización , Conformación Molecular , Estereoisomerismo
11.
Chemistry ; 12(6): 1677-93, 2006 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-16358351

RESUMEN

Gold(I) complexes are the most active catalysts for alkoxy- or hydroxycyclization and for skeletal rearrangement reactions of 1,6-enynes. Intramolecular alkoxycyclizations also proceed efficiently in the presence of gold(I) catalysts. The first examples of the skeletal rearrangement of enynes by the endocyclic cyclization pathway are also documented. Iron(III) is also able to catalyze exo and endo skeletal rearrangements of 1,6-enynes, although the scope of this transformation is more limited. The gold(I)-catalyzed endocyclic cyclization proceeds by a mechanism different from those followed in the presence of PdII, HgII, or RhI catalysts.

12.
Chemistry ; 12(6): 1694-702, 2006 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-16358352

RESUMEN

Gold(I) complexes are the most active catalysts for the biscyclopropanation of dienynes to form tetracyclic compounds. PtII and ZnII are also able to promote the biscyclopropanation, although less efficiently. The configurations obtained in all cases with the use of gold(I) catalysts can be explained by the pathway proceeding through anti cyclopropyl gold carbenes. Similar intermediates are most probably involved in reactions catalyzed by RuII and PtII. Two different cyclopropanation pathways have been found; they depend on the structures of the cyclopropyl gold carbenes (anti or syn) and the relative arrangements of the metal carbenes and the alkenes.

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