Selectivity profiles and substrate recognition of Rab-phosphorylating kinases.

The Rab GTPase switch-2 region is a hotspot for post-translational modifications. Its phosphorylation can determine whether individuals develop Parkinson's disease or not. Other modifications of the same region are catalyzed by enzymes from bacterial pathogens when they infect human cells.

Co-design of Active Material and Solid Electrolyte Particulate Phases in Solid-State Battery Composite Electrodes.

The performance of solid-state batteries (SSBs) is strongly influenced by the solid-state cathode architecture, particularly the particle sizes of the active material (AM) and solid electrolyte (SE). While smaller SE particles are known to consistently enhance composite-level effective ionic transport, the underpinning role of the AM particle size remains unclear. Although smaller AM particles are often assumed to enhance the rate capability, some experimental observations have shown conflicting trends.

Imidazopyrimidine-based pyruvate kinase M2 activator halts diabetic nephropathy progression via modulating epithelial-to-mesenchymal transition and fibrosis.

Diabetic nephropathy affects nearly 40 % of diabetic patients, causing kidney damage through metabolic dysregulation and the build-up of toxic glucose metabolites. Upregulated pyruvate kinase M2 (PKM2) promotes glycolysis, activates hypoxia-inducible factor-1 (HIF-1), and induces epithelial-to-mesenchymal transition (EMT), collectively driving renal fibrosis and dysfunction. The dimeric form of PKM2 amplifies inflammation, while its tetrameric form protects against DN.

IMID-284: a potent pyruvate kinase M2 inhibitor with dual anti-inflammatory and analgesic effects in intervertebral disc disease.

Purpose: Intervertebral disc degeneration (IVDD) is a major contributor to lower back pain and disability, driven by alterations in extracellular matrix (ECM) remodelling and inflammation following chondroptosis. While the relationship between IVDD and ECM biochemical changes is well-established, the specific role of pyruvate kinase M2 (PKM2) in this process remains unexplored. This study aimed to investigate the involvement of PKM2 in a Chondroitinase ABC (ChABC)-induced model of IVDD.

Type II kinase inhibitors that target Parkinson's disease-associated LRRK2.

Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowledge, we present the first type II kinase inhibitors that target LRRK2.

Synthesis, characterization, and microbiological evaluation of new triazolopyrimidine-based ferrocenes as potent antimicrobial prospects.

Antimicrobial metallodrugs have gained considerable attention for their potent inhibitory activity and clinical success, driving the development of novel metallodrug candidates. These efforts have uncovered new bioactive scaffolds and mechanisms of action. However, the global challenge of antimicrobial resistance (AMR), fueled by the genetic adaptability of microbes and resistance to nearly all antibiotic classes, highlights the urgent need for innovative antibiotics.

Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor.

Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds to an allosteric pocket created by an αC-out/DFG-out conformation. This inactive conformation results in a large expansion of the kinase back pocket, a conformation that has also been reported for LIM kinases.

Correction: LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains.

[This corrects the article DOI: 10.1371/journal.pbio.

Development of novel tetrazole-based pyruvate kinase M2 inhibitors targeting U87MG glioblastoma cells.

Glioblastoma (GB), the most aggressive and life-threatening primary brain tumor in adults, poses significant therapeutic challenges. Tumor pyruvate kinase M2 (PKM2) has been implicated in the proliferation and survival of glioma cells. In this study, we designed and synthesized a series of 23 novel tetrazole-based derivatives.

Type-II kinase inhibitors that target Parkinson's Disease-associated LRRK2.

Aberrant increases in kinase activity of leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD). Numerous LRRK2-selective type-I kinase inhibitors have been developed and some have entered clinical trials. In this study, we present the first LRRK2-selective type-II kinase inhibitors.

Novel sulfonamides unveiled as potent anti-lung cancer agents tumor pyruvate kinase M2 activation.

This rational pursuit led to the identification of a novel sulfonamide derivative as a potent anti-lung cancer (LC) compound. Considering these results, we synthesized 38 novel sulfonamide derivatives with diverse skeletal structures. cytotoxicity assays revealed a potent and selective antiproliferative effect against A549 cells after evaluating a panel of cancer cell lines.

A designed ankyrin-repeat protein that targets Parkinson's disease-associated LRRK2.

Leucine rich repeat kinase 2 (LRRK2) is a large multidomain protein containing two catalytic domains, a kinase and a GTPase, as well as protein interactions domains, including a WD40 domain. The association of increased LRRK2 kinase activity with both the familial and sporadic forms of Parkinson's disease has led to an intense interest in determining its cellular function. However, small molecule probes that can bind to LRRK2 and report on or affect its cellular activity are needed.

Tetrahydropyridine LIMK inhibitors: Structure activity studies and biological characterization.

LIM Kinases, LIMK1 and LIMK2, have become promising targets for the development of inhibitors with potential application for the treatment of several major diseases. LIMKs play crucial roles in cytoskeleton remodeling as downstream effectors of small G proteins of the Rho-GTPase family, and as major regulators of cofilin, an actin depolymerizing factor. In this article we describe the conception, synthesis, and biological evaluation of novel tetrahydropyridine pyrrolopyrimidine LIMK inhibitors.

Mechanistic Investigation of Thiazole-Based Pyruvate Kinase M2 Inhibitor Causing Tumor Regression in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a deadly breast cancer with a poor prognosis. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, is abnormally highly expressed in TNBC. Overexpressed PKM2 amplifies glucose uptake, enhances lactate production, and suppresses autophagy, thereby expediting the progression of oncogenic processes.

Comprehensive characterization and preclinical assessment of an imidazopyridine-based anticancer lead molecule.

Imidazopyridine scaffold holds significant pharmacological importance in the treatment of cancer. An in-house synthesized imidazopyridine-based molecule was found to have promising anticancer activity against breast cancer, lung cancer, and colon cancer. The molecule is an inhibitor of pyruvate kinase M2, the enzyme that elevates tumor growth, metastasis and chemoresistance by directly controlling tumor cell metabolism.

Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with both familial and sporadic PD, making LRRK2 kinase inhibitors a major focus of drug development efforts. Although much progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes.

Structure of LRRK1 and mechanisms of autoinhibition and activation.

Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, their disease associations are strikingly different: LRRK2 is involved in familial Parkinson's disease while LRRK1 is linked to bone diseases. Furthermore, Parkinson's disease-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function.

Roadmap to Pyruvate Kinase M2 Modulation - A Computational Chronicle.

Pyruvate kinase M2 (PKM2) has surfaced as a potential target for anti-cancer therapy. PKM2 is known to be overexpressed in the tumor cells and is a critical metabolic conduit in supplying the augmented bioenergetic demands of the recalcitrant cancer cells. The presence of PKM2 in structurally diverse tetrameric as well as dimeric forms has opened new avenues to design novel modulators.

PROTACting the kinome with covalent warheads.

The dawn of targeted degradation using proteolysis-targeting chimeras (PROTACs) against recalcitrant proteins has prompted numerous efforts to develop complementary drugs. Although many of these are specifically directed against undruggable proteins, there is increasing interest in small molecule-based PROTACs that target intracellular pathways, and some have recently entered clinical trials. Concurrently, small molecule-based PROTACs that target protumorigenic pathways in cancer cells, the tumor microenvironment (TME), and angiogenesis have been found to have potent effects that synergize with the action of antibodies.

Identification and Biochemical Characterization of Pyrrolidinediones as Novel Inhibitors of the Bacterial Enzyme MurA.

To develop novel antibiotics, targeting the early steps of cell wall peptidoglycan biosynthesis seems to be a promising strategy that is still underutilized. MurA, the first enzyme in this pathway, is targeted by the clinically used irreversible inhibitor fosfomycin. However, mutations in its binding site can cause bacterial resistance.

PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain.

Leucine-rich-repeat-kinase 1 (LRRK1) and its homolog LRRK2 are multidomain kinases possessing a ROC-CORA-CORB containing GTPase domain and phosphorylate distinct Rab proteins. LRRK1 loss of function mutations cause the bone disorder osteosclerotic metaphyseal dysplasia, whereas LRRK2 missense mutations that enhance kinase activity cause Parkinson's disease. Previous work suggested that LRRK1 but not LRRK2, is activated via a Protein Kinase C (PKC)-dependent mechanism.

Illuminating the Dark: Highly Selective Inhibition of Serine/Threonine Kinase 17A with Pyrazolo[1,5-]pyrimidine-Based Macrocycles.

Serine/threonine kinase 17A (death-associated protein kinase-related apoptosis-inducing protein kinase 1─DRAK1) is a part of the death-associated protein kinase (DAPK) family and belongs to the so-called dark kinome. Thus, the current state of knowledge of the cellular function of DRAK1 and its involvement in pathophysiological processes is very limited. Recently, DRAK1 has been implicated in tumorigenesis of glioblastoma multiforme (GBM) and other cancers, but no selective inhibitors of DRAK1 are available yet.

Enabling pseudokinases as potential drug targets.

Pseudokinases play significant roles in disease development. Similar to active kinases, their cellular functions can be targeted pharmacologically. But notably, instead of inhibiting an enzymatic activity, drug-like molecules act by stabilizing distinct pseudokinase conformations, by interfering with protein interactions, or by inducing proteasomal degradation.