Structure–activity studies of a series of dipyrazolo[3,4- b :3′,4′- d ]pyridin-3-ones binding to the immune regulatory protein B7.1

Green, Neal J.; Xiang, Jason; Chen, Jing; Chen, Lih-Ren; Davies, Audrey M.; Erbe, Dave; Tam, S. William; Tobin, James F.

doi:10.1016/s0968-0896(03)00183-4

Cited by 37 publications

(35 citation statements)

References 30 publications

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“…A follow‐up study on understanding the structure‐activity relationships (SAR) of the small molecules based dipyrazolo[3,4‐b:3′,4′‐d] pyridine‐3‐ones was reported. As part of this effort, several derivatives of compound 1 (Figure A) were synthesized and their activity toward inhibiting the hB7‐1:CD28 interaction was evaluated using the ELISA technique.…”

Section: Discovery and Development Of Small‐molecule Inhibitors Of Humentioning

confidence: 96%

“…As part of this effort, several derivatives of compound 1 (Figure A) were synthesized and their activity toward inhibiting the hB7‐1:CD28 interaction was evaluated using the ELISA technique. This study revealed that the core structure of compound 1 (Figure A), which encompassed a dipyrazolopyridine group, a chlorbenzene group (or the northern ring) and a 3‐trifluoromethylphenyl group (or the southern ring), was important for favorable activity. For example, removal of the northern ring or substituting it with alkyl groups led to a complete loss of activity .…”

Section: Discovery and Development Of Small‐molecule Inhibitors Of Humentioning

confidence: 96%

“…Efforts to design small‐molecule inhibitors targeting the CD28:B7 interactions began during the late nineties . Although initial efforts resulted in either weak or nonspecific inhibitors, a major breakthrough came from Wyeth Research (part of Pfizer Inc).…”

Section: Discovery and Development Of Small‐molecule Inhibitors Of Humentioning

confidence: 99%

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Targeting B7‐1 in immunotherapy

Chen

Okoye

Arutyunova

et al. 2019

Medicinal Research Reviews

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Modulation of T‐cell immune functions by blocking key immune checkpoint protein interactions using monoclonal antibodies (mAbs) has been an innovative immunotherapeutic strategy. T‐cells are regulated by different checkpoint proteins at the immunological synapse including the B7 ligands (B7‐1 or CD80 and B7‐2 or CD86), which is discussed in this review. These ligands are typically expressed on antigen presenting cells and interact with CD28 and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) receptors on T‐cells. Their interactions with CD28 trigger a costimulatory signal that potentiates T‐cell activation, function and survival in response to cognate antigen. In addition, their interactions with CTLA‐4 can also inhibit certain effector T‐cell responses, particularly in response to sustained antigen stimulation. Through these mechanisms, the balance between T‐cell activation and suppression is maintained, preventing the occurrence of immunopathology. Given their crucial roles in immune regulation, targeting B7 ligands has been an attractive strategy in cancer and autoimmunity. This review presents an overview of the essential roles of B7‐1, highlighting the therapeutic benefits of modulating this protein in immunotherapy, and reviewing earlier and state‐of‐the‐art efforts in developing anti‐B7‐1 inhibitors. Finally, we discuss the challenges facing the design of selective B7‐1 inhibitors and present our perspectives for future developments.

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Section: Discovery and Development Of Small‐molecule Inhibitors Of Humentioning

confidence: 96%

Section: Discovery and Development Of Small‐molecule Inhibitors Of Humentioning

confidence: 96%

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Targeting B7‐1 in immunotherapy

Chen

Okoye

Arutyunova

et al. 2019

Medicinal Research Reviews

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“…The presence of hot spots and hot regions within protein interfaces provide possible sites at which potent small-molecule inhibitors may bind to effectively block the association of much larger molecules. Indeed, small peptides selected by phage display generally bind their protein binding partners at hot spots (41), and the discovery of small molecules that inhibit the interaction of B7-1 with CD28 and modulate T cell activation, and in which the drug binds at a hot spot, has been reported (42,43). If certain distinct hot regions may be linked energetically, as our results suggest, the potency of a small-molecule inhibitor that targets a cooperative hot region may be amplified relative to a small molecule that targets a hot region that is strictly additive.…”

Section: Implications For Protein-protein Interaction Prediction and mentioning

confidence: 99%

Long-range cooperative binding effects in a T cell receptor variable domain

Moza

Buonpane

Zhu

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Although cellular processes depend on protein-protein interactions, our understanding of molecular recognition between proteins remains far from comprehensive. Protein-protein interfaces are structural and energetic mosaics in which a subset of interfacial residues, called hot spots, contributes disproportionately to the affinity of the complex. These hot-spot residues can be further clustered into hot regions. It has been proposed that binding energetics between residues within a hot region are cooperative, whereas those between hot regions are strictly additive. If this idea held true for all protein-protein interactions, then energetically significant long-range conformational effects would be unlikely to occur. In the present study, we show cooperative binding energetics between distinct hot regions that are separated by >20 Å. Using combinatorial mutagenesis and surface plasmon resonance binding analysis to dissect additivity and cooperativity in a complex formed between a variable domain of a T cell receptor and a bacterial superantigen, we find that combinations of mutations from each of two hot regions exhibited significant cooperative energetics. Their connecting sequence is composed primarily of a single ␤-strand of the T cell receptor variable Ig domain, which has been observed to undergo a strand-switching event and does not form an integral part of the stabilizing core of this Ig domain. We propose that these cooperative effects are propagated through a dynamic structural network. Cooperativity between hot regions has significant implications for the prediction and inhibition of protein-protein interactions.binding energy ͉ cooperativity ͉ protein-protein interaction ͉ surface plasmon resonance ͉ T cell activity

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“…Most of these inhibitors are far from being druglike . Nevertheless, there have also small and some druglike molecules been developed that inhibit protein–protein interactions efficiently, for instance, the interaction between (1) p53 and MDM2,12, 13 (2) Bcl‐xL and Bcl‐2,14, 15 both playing a crucial role in cell apoptosis,16, 17 and (3) IL‐2 and the α subunit of its receptor (IL‐2Rα),18 (4) CTLA4 and B7‐2,19 both important for T‐cell proliferation 20. Despite these outstanding successes, the mentioned protein–protein interactions addressed in these examples by small molecules exhibit special features that unlikely allow to generalize them into a common inhibition strategy.…”

Section: Introductionmentioning

confidence: 99%

Strategies to search and design stabilizers of protein–protein interactions: A feasibility study

et al. 2007

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Since protein-protein interactions play a pivotal role in the communication on the molecular level in virtually every biological system and process, the search and design for modulators of such interactions is of utmost importance. In recent years many inhibitors for specific protein-protein interactions have been developed, however, in only a few cases, small and druglike molecules are able to interfere in the complex formation of proteins. On the other hand, there are several small molecules known to modulate protein-protein interactions by means of stabilizing an already assembled complex. To achieve this goal, a ligand is binding to a pocket, which is located rim-exposed at the interface of the interacting proteins, for example as the phytotoxin Fusicoccin, which stabilizes the interaction of plant H+-ATPase and 14-3-3 protein by nearly a factor of 100. To suggest alternative leads, we performed a virtual screening campaign to discover new molecules putatively stabilizing this complex. Furthermore, we screen a dataset of 198 transient recognition protein-protein complexes for cavities, which are located rim-exposed at their interfaces. We provide evidence for high similarity between such rim-exposed cavities and usual ligands accommodating active sites of enzymes. This analysis suggests that rim-exposed cavities at protein-protein interfaces are druggable binding sites. Therefore, the principle of stabilizing protein-protein interactions seems to be a promising alternative to the approach of the competitive inhibition of such interactions by small molecules.

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Structure–activity studies of a series of dipyrazolo[3,4- b :3′,4′- d ]pyridin-3-ones binding to the immune regulatory protein B7.1

Cited by 37 publications

References 30 publications

Targeting B7‐1 in immunotherapy

Targeting B7‐1 in immunotherapy

Long-range cooperative binding effects in a T cell receptor variable domain

Strategies to search and design stabilizers of protein–protein interactions: A feasibility study

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