Search Results (61)

Phosphatidylinositol 3-kinase alpha (PI3Kα) is frequently mutated in head and neck squamous cell carcinoma (HNSCC), leading to the constitutive activation of the PI3K/Akt pathway, which promotes tumor cell proliferation, survival, and metastasis. PI3Kα allosteric inhibitors demonstrate therapeutic potential as both monotherapy and combination therapy, particularly in patients with PIK3CA mutations or resistance to immunotherapy, through the precise targeting of mutant PI3Kα. Compared to ATP-competitive PI3Kα inhibitors such as Alpelisib, the allosteric inhibitor RLY-2608 exhibits enhanced selectivity for mutant PI3Kα while minimizing the inhibition of wild-type PI3Kα, thereby reducing side effects such as hyperglycemia. To date, no allosteric PI3Kα inhibitors have been approved for clinical use. To develop novel PI3Kα inhibitors with improved safety and efficacy, we employed a scaffold hopping approach to structurally modify RLY-2608 and constructed a compound library. Based on the structural information of the PI3Kα allosteric site, we conducted the systematic virtual screening of 11,550 molecules from databases to identify lead compounds. Through integrated approaches, including molecular docking studies, target validation, druggability evaluation, molecular dynamics simulations, and metabolic pathway and metabolite analyses, we successfully identified a promising novel allosteric PI3Kα inhibitor, H-18 (3-(2-chloro-5-fluorophenyl)isoindolin-1-one). H-18 has not been previously reported as a PI3Kα inhibitor, and provides an excellent foundation for subsequent lead optimization, offering a significant starting point for the development of more potent PI3Kα allosteric inhibitors. Full article

Deucravacitinib, a selective oral tyrosine kinase 2 (TYK2) inhibitor, has demonstrated strong efficacy in the treatment of moderate-to-severe psoriasis. It works through an allosteric mechanism to selectively inhibit TYK2, leading to the suppression of the IL-23/Th17/IL-17 axis and a reduction in key pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22, and IL-23. This review focuses on the clinical implications of deucravacitinib in East Asian patients, highlighting its efficacy, safety, and differences in treatment outcomes compared to other populations. Data from pivotal trials such as POETYK PSO-3 and PSO-4, which included East Asian populations, demonstrated robust efficacy and safety profiles, often surpassing results observed in global trials like POETYK PSO-1 and PSO-2. Subgroup analyses and network meta-analyses further corroborate these findings, providing a comprehensive understanding of its therapeutic potential in this demographic. Factors such as lower body mass index, genetic predispositions, and environmental influences may contribute to these differences in response. The safety profile of deucravacitinib is favorable, with low rates of serious adverse events and stable laboratory parameters. This review underscores the need for further research to investigate the genetic, metabolic, and environmental factors that may influence treatment outcomes, aiming to optimize personalized treatment strategies for East Asian patients with psoriasis. Full article

Deucravacitinib is an allosteric, selective tyrosine kinase 2 (TYK2) inhibitor that has demonstrated significant efficacy in the treatment of psoriasis. TYK2, a member of the Janus kinase (JAK) family, plays a critical role in intracellular signaling pathways for pro-inflammatory cytokines. Unlike traditional JAK inhibitors, which target active domains, deucravacitinib selectively binds to the pseudokinase domain of TYK2. This binding induces a conformational change that locks the enzyme in an inactive state, ensuring superior selectivity for TYK2 over JAK 1/2/3. This unique mechanism specifically inhibits key pro-inflammatory cytokines, including IL-12, IL-23, and type I interferons, critical in the pathogenesis of psoriasis and other immune-mediated diseases. As a result, deucravacitinib represents a promising option for targeted therapy in immune-mediated diseases and may reduce adverse events commonly associated with broader immunosuppressive treatments. Furthermore, its oral administration offers a convenient alternative to injectable biologics, potentially improving patient adherence and treatment satisfaction. This review highlights recent studies suggesting that deucravacitinib may also have therapeutic benefits in psoriatic arthritis, palmoplantar pustulosis, systemic lupus erythematosus, Sjogren’s disease, and inflammatory bowel disease. Given its expanding therapeutic potential, deucravacitinib may provide a safer and more effective alternative to current therapies, offering a tailored approach to treatment. Full article

BCR-ABL1 kinase is a critical driver of chronic myeloid leukemia (CML) pathophysiology. The approval of allosteric inhibitor asciminib brings new hope for overcoming drug resistance caused by mutations in the ATP-binding site. To expand the chemical diversity of BCR-ABL1 kinase inhibitors with positive anti-tumor effect with asciminib, structure-based virtual screening and molecular dynamics simulations were employed to discover novel scaffolds. This approach led to the identification of a series of N-(2-acetamidobenzo[d]thiazol-6-yl)-2-phenoxyacetamide derivatives as new BCR-ABL1 inhibitors. The most potent compound, 10m, demonstrated inhibition of BCR-ABL-dependent signaling and showed an anti-tumor effect against K562 cells, with an IC₅₀ value of 0.98 μM. Compound 10m displayed powerful synergistic anti-proliferation and pro-apoptotic effects when combined with asciminib, highlighting its potential as a promising lead for the development of potential BCR-ABL inhibitors. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC₅₀ values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies. Full article

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). Full article

Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) regulate the level of tyrosine phosphorylation in proteins. PTKs are key enzymes that catalyze the transfer of an ATP phosphoric acid to a tyrosine residue on target protein substrates. Protein tyrosine phosphatases (PTPs) are responsible for the dephosphorylation of tyrosine residues and play a role in countering PTK overactivity. As widespread oncogenes, PTKs were once considered to be promising targets for therapy. However, tyrosine kinase inhibitors (TKIs) now face a number of challenges, including drug resistance and toxic side effects. Treatment strategies now need to be developed from a new perspective. In this review, we assess the current state of TKIs and highlight the role of PTPs in cancer and other diseases. With the advances of allosteric inhibition and the development of multiple alternative proprietary drug strategies, the reputation of PTPs as “undruggable” targets has been overturned, and they are now considered viable therapeutic targets. We also discuss the strategies and prospects of PTP-targeted therapy, as well as its future development. Full article

SHP2, a pivotal component downstream of both receptor and non-receptor tyrosine kinases, has been underscored in the progression of various human cancers and neurodevelopmental disorders. Allosteric inhibitors have been proposed to regulate its autoinhibition. However, oncogenic mutations, such as E76K, convert SHP2 into its open state, wherein the catalytic cleft becomes fully exposed to its ligands. This study elucidates the dynamic properties of SHP2 structures across different states, with a focus on the effects of oncogenic mutation on two known binding sites of allosteric inhibitors. Through extensive modeling and simulations, we further identified an alternative allosteric binding pocket in solution structures. Additional analysis provides insights into the dynamics and stability of the potential site. In addition, multi-tier screening was deployed to identify potential binders targeting the potential site. Our efforts to identify a new allosteric site contribute to community-wide initiatives developing therapies using multiple allosteric inhibitors to target distinct pockets on SHP2, in the hope of potentially inhibiting or slowing tumor growth associated with SHP2. Full article

The allosteric inhibition of insulin-like growth factor receptor 1 kinase (IGF1RK) is a potential strategy to overcome selectivity barriers for targeting receptor tyrosine kinases. We constructed structural models of a series of 12 indole-butyl-amine derivatives that have been reported as allosteric inhibitors of IGF1RK. We further studied the dynamics and interactions of each inhibitor in the allosteric pocket via all-atom explicit-solvent molecular dynamics (MD) simulations. We discovered that a bulky carbonyl substitution at the R1 indole ring is structurally unfavorable for inhibitor binding in the IGF1RK allosteric pocket. Moreover, we found that the most potent derivative (termed C11) acquires a distinct conformation: forming an allosteric pocket channel with better shape complementarity and interactions with the receptor. In addition to a hydrogen-bonding interaction with V1063, the cyano derivative C11 forms a stable hydrogen bond with M1156, which is responsible for its unique binding conformation in the allosteric pocket. Our findings show that the positioning of chemical substituents with different pharmacophore features at the R1 indole ring influences molecular interactions and binding conformations of indole-butyl-amine derivatives and, hence, dramatically affects their potencies. Our results provide a structural framework for the design of allosteric inhibitors with improved affinities and specificities against IGF1RK. Full article

Protein kinases are essential regulators of cell function and represent one of the largest and most diverse protein families. They are particularly influential in signal transduction and coordinating complex processes like the cell cycle. Out of the 518 human protein kinases identified, 478 are part of a single superfamily sharing catalytic domains that are related in sequence. The dysregulation of protein kinases due to certain mutations has been associated with various diseases, including cancer. Although most of the protein kinase inhibitors identified as type I or type II primarily target the ATP-binding pockets of kinases, the structural and sequential resemblances among these pockets pose a significant challenge for selective inhibition. Therefore, targeting allosteric pockets that are beside highly conserved ATP pockets has emerged as a promising strategy to prevail current limitations, such as poor selectivity and drug resistance. In this article, we compared the binding pockets of various protein kinases for which allosteric (type III) inhibitors have already been developed. Additionally, understanding the structure and shape of existing ligands could aid in identifying key interaction sites within the allosteric pockets of kinases. This comprehensive review aims to facilitate the design of more effective and selective allosteric inhibitors. Full article

The fibroblast growth factor receptor 2 (FGFR2) gene is one of the most extensively studied genes with many known mutations implicated in several human disorders, including oncogenic ones. Most FGFR2 disease-associated gene mutations are missense mutations that result in constitutive activation of the FGFR2 protein and downstream molecular pathways. Many tertiary structures of the FGFR2 kinase domain are publicly available in the wildtype and mutated forms and in the inactive and activated state of the receptor. The current literature suggests a molecular brake inhibiting the ATP-binding A loop from adopting the activated state. Mutations relieve this brake, triggering allosteric changes between active and inactive states. However, the existing analysis relies on static structures and fails to account for the intrinsic structural dynamics. In this study, we utilize experimentally resolved structures of the FGFR2 tyrosine kinase domain and machine learning to capture the intrinsic structural dynamics, correlate it with functional regions and disease types, and enrich it with predicted structures of variants with currently no experimentally resolved structures. Our findings demonstrate the value of machine learning-enabled characterizations of structure dynamics in revealing the impact of mutations on (dys)function and disorder in FGFR2. Full article

Protein kinase B (PKB) or AKT protein is an important target for cancer treatment. Significant advances have been made in developing ATP-competitive inhibitors and allosteric binders targeting AKT1. However, adverse effects or toxicities have been found, and the cutaneous toxicity was found to be linked to the inhibition of AKT2. Thus, selective inhibition of AKT inhibitors is of significance. Our work, using the Schrödinger Covalent Dock (CovDock) program and the Movable Type (MT)-based free energy calculation (ΔG), yielded small mean errors for the experimentally derived binding free energy (ΔG). The docking data suggested that AKT1 binding may require residues Asn54, Trp80, Tyr272, Asp274, and Asp292, whereas AKT2 binding would expect residues Phe163 and Glu279, and AKT3 binding would favor residues Glu17, Trp79, Phe306, and Glu295. These findings may help guide AKT1-selective or AKT3-selective molecular design while sparing the inhibition of AKT2 to minimize the cutaneous toxicity. Full article

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells. Full article

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity. Full article

In drug discovery, protein kinase inhibitors (PKIs) are intensely investigated as drug candidates in different therapeutic areas. While ATP site-directed, non-covalent PKIs have long been a focal point in protein kinase (PK) drug discovery, in recent years, there has been increasing interest in allosteric PKIs (APKIs), which are expected to have high kinase selectivity. In addition, as compounds acting by covalent mechanisms experience a renaissance in drug discovery, there is also increasing interest in covalent PKIs (CPKIs). There are various reasons for this increasing interest such as the anticipated high potency, prolonged residence times compared to non-competitive PKIs, and other favorable pharmacokinetic properties. Due to the popularity of PKIs for therapeutic intervention, large numbers of PKIs and large volumes of activity data have accumulated in the public domain, providing a basis for large-scale computational analysis. We have systematically searched for CPKIs containing different reactive groups (warheads) and investigated their potency and promiscuity (multi-PK activity) on the basis of carefully curated activity data. For seven different warheads, sufficiently large numbers of CPKIs were available for detailed follow-up analysis. For only three warheads, the median potency of corresponding CPKIs was significantly higher than of non-covalent PKIs. However, for CKPIs with five of seven warheads, there was a significant increase in the median potency of at least 100-fold compared to PKI analogues without warheads. However, in the analysis of multi-PK activity, there was no general increase in the promiscuity of CPKIs compared to non-covalent PKIs. In addition, we have identified 29 new APKIs in X-ray structures of PK-PKI complexes. Among structurally characterized APKIs, 13 covalent APKIs in complexes with five PKs are currently available, enabling structure-based investigation of PK inhibition by covalent-allosteric mechanisms. Full article