RESUMO
The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed against additional checkpoint proteins, there is an increasing interest in small-molecule immuno-oncology drugs that address intracellular pathways, some of which have recently entered clinical trials. In parallel, small molecules that target pro-tumorigenic pathways in cancer cells and the tumour microenvironment have been found to have immunostimulatory effects that synergize with the action of ICI antibodies, leading to the approval of an increasing number of regimens that combine such drugs. Combinations with small molecules targeting cancer metabolism, cytokine/chemokine and innate immune pathways, and T cell checkpoints are now under investigation. This Review discusses the recent milestones and hurdles encountered in this area of drug development, as well as our views on the best path forward.
Assuntos
Imunoterapia , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Microambiente Tumoral , Citocinas , Linfócitos TRESUMO
The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool MSC-4106, which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time- and dose-dependent downregulation of a proximal biomarker could be shown.
Assuntos
Neoplasias , Fatores de Transcrição , Animais , Camundongos , Fatores de Transcrição de Domínio TEA , Fatores de Transcrição/metabolismoRESUMO
Immuno-oncology therapies are revolutionizing the oncology landscape with checkpoint blockade becoming the treatment backbone for many indications. While inspiring, much work remains to increase the number of cancer patients that can benefit from these treatments. Thus, a new era of immuno-oncology research has begun which is focused on identifying novel combination regimes that lead to improved response rates. This review highlights the significance of small molecules in this approach and illustrates the huge progress that has been made to date.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Aminoácidos/antagonistas & inibidores , Aminoácidos/imunologia , Antineoplásicos/química , Humanos , Neoplasias/imunologia , Inibidores de Proteínas Quinases/química , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Immuno-oncology therapies have the potential to revolutionize the armamentarium of available cancer treatments. To further improve clinical response rates, researchers are looking for novel combination regimens, with checkpoint blockade being used as a backbone of the treatment. This Review highlights the significance of small molecules in this approach, which holds promise to provide increased benefit to cancer patients.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Humanos , Neoplasias/patologiaRESUMO
A divergent approach to enantioenriched 2H- and 3H-pyrroles catalyzed by a spirocyclic phosphoric acid is reported that makes use of a Fischer-type indolization and a [1,5]-alkyl shift. Catalyzed by the chiral phosphoric acid STRIP, good to excellent yields and enantioselectivities could be obtained. Remarkably, biological evaluation reveals one of these novel 2H-pyrroles to be a potent but nontoxic inhibitor of the Hedgehog signaling pathway by binding to the Smoothened protein.
Assuntos
Proteínas Hedgehog/metabolismo , Pirróis/metabolismo , Compostos de Boro/química , Catálise , Cristalografia por Raios X , Células HEK293 , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Microscopia de Fluorescência , Conformação Molecular , Ácidos Fosfóricos/química , Pirróis/química , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , EstereoisomerismoRESUMO
In the title free base porphyrin, C42H34N4, the neighbouring Nâ¯N distances in the center of the ring vary from 2.818â (8) to 2.998â (8)â Å and the phenyl rings are tilted from the 24-atom mean plane at angles varying between 62.42â (2)-71.63â (2)°. The NH groups are involved in intra-molecular bifurcated N-Hâ¯(N,N) hydrogen bonds. The Ca-Cm-Ca angles vary slightly for the phenyl rings, between 124.19â (18)-126.17â (18)°. The largest deviation from the mean plane of the 24-atom macrocycle is associated with the meso carbon at the substituted tert-butyl position, which is displaced from the mean plane by 0.44â (2)â Å. The free base porphyrin is characterized by a significant degree of ruffled (B 1u ) distortion with contributions from domed (A 2u ) and wave [Eg (y) and Eg (x)] modes. In the crystal, mol-ecules are linked by a number of weak C-Hâ¯π inter-actions, forming a three-dimensional framework. The structure was refined as a two-component inversion twin.
RESUMO
The asymmetric unit of the title nickel(II) porphyrin, [Ni(C48H60N4O2)], contains one independent mol-ecule. The average Ni-N bond length is 1.917â (13)â Å. The mol-ecules are arranged in a closely spaced lattice structure in which neighbouring porphyrins are oriented in inversion-related dimers. The nickel(II) porphyrin is characterized by a significant degree of a ruffled (B 1u ) conformation with small contributions from saddle (B 2u ) and wave (y) [Eg (y)], as determined using normal structural decomposition. Disorder in the 2,5-di--meth-oxy-phenyl substituent was modelled over two positions with a 60% occupancy for the major moiety. One of the ethyl groups is also disordered over two positions and was modelled with the major moiety being present in 51.3% occupancy.
RESUMO
An asymmetric Brønsted acid catalyzed dearomatizing redox cross coupling reaction has been realized, in which aryl hydrazines react with ketones to deliver 1,4-diketones, bearing an all-carbon quarternary stereocenter in high enantiopurity.
RESUMO
The first asymmetric organocatalytic synthesis of helicenes is reported. A novel SPINOL-derived phosphoric acid, bearing extended π-substituents, catalyzes the asymmetric synthesis of helicenes through an enantioselective Fischer indole reaction. A variety of azahelicenes and diazahelicenes could be obtained with good to excellent yields and enantioselectivities.