Artifacts generated during sample preparation or analysis can compromise impurity evaluation in pharmaceutical quality control. Lenalidomide, a thalidomide derivative used for multiple myeloma treatment and as a cereblon ligand in a proteolysis-targeting chimera (PROTAC), undergoes methanolysis through ring opening of its glutarimide moiety, forming constitutional isomers. This study systematically evaluated the alcoholysis of lenalidomide under various pH, methanol (MeOH) concentration, temperature, and alcohol conditions to clarify key factors affecting artifact formation. Stress studies showed that the total amount of methanolysis products exhibited linear relationships with pH, MeOH concentration, and temperature after log transformation. Kinetic modeling indicated that pH had the strongest effect on degradation, followed by MeOH concentration and temperature. The reaction was markedly accelerated under basic conditions, likely due to nucleophilic attack by methoxide ions. Evaluation of monohydric alcohols revealed that MeOH produced the greatest amount of alcoholysis products, whereas longer-chain and branched alcohols showed lower reactivity. In particular, 2-propanol effectively suppressed product formation, probably because of steric hindrance. These results demonstrate the importance of controlling pH and solvent composition during analysis to minimize artifact formation. The findings provide practical strategies for improving impurity assessment methods for lenalidomide and related thalidomide derivatives, including cereblon-recruiting PROTACs.

Immune checkpoint inhibitors (ICIs), including novel bispecific antibodies targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have expanded therapeutic options but have also increased the incidence and complexity of immune-related adverse events (irAEs). Low-dose interleukin-2 (Ld-IL2) has been explored as a potential immunomodulatory strategy. However, its role in real-world combination regimens for managing severe cutaneous irAEs remains to be fully elucidated. We report the case of a patient with gastric cancer who developed rapidly progressive erythema and pruritus after treatment with iparomlimab and tuvonralimab. Symptoms worsened despite corticosteroids, intravenous immunoglobulin (IVIG) and antihistamines. After Ld-IL2 and thalidomide were added while corticosteroid treatment was continued, clinical improvement was observed within 48 hours, with complete resolution of the skin lesions at 2 weeks. Because Ld-IL2, thalidomide, and corticosteroids were administered concurrently, the independent contribution of each treatment and the underlying immunological mechanism could not be determined. However, further studies are warranted to clarify the potential value of this combined regimen in the management of such adverse events.

Kinase inhibitors are a cornerstone of modern drug discovery, with more than 100 approved compounds which have had a transformative impact in precision oncology and inflammatory disease. Their success has rested largely on small-molecule control of catalytic activity through ATP-site engagement; a framework that leaves important biology unaddressed, including non-catalytic kinase functions, resistance driven by active-site mutation, and the limits of selectivity imposed by pocket conservation. Against this backdrop, the observation that kinase inhibitors can reduce target protein abundance has gained new mechanistic depth. Chaperone deprivation, supercharging of native degradation circuits, and context-dependent mutant-selective depletion mark distinct routes through which inhibitor binding can intersect with cellular proteostasis. The kinase inhibitor CR8 extends this logic into chemically encoded degradation: CR8 acts as a molecular glue degrader by creating, within the ligand-bound kinase complex, a composite surface that directly recruits a ubiquitin ligase, resulting in cyclin K degradation. Thalidomide analogues can degrade kinases through scaffolds that do not bind the kinase in isolation: ligase-binding compounds that recruit neosubstrate kinases through recognition of structural surface degrons. Deliberately engineered PROTACs encode ligase-target proximity through heterobifunctional architecture to convert kinase binders into degraders. Beyond degradation, induced-proximity mechanisms - from the clinically established rapamycin to bifunctional molecules that redirect kinase activity or restrict inhibition to tumour cells - show how small molecules can reshape kinase interaction states rather than simply block active sites. Together, these examples define an expanding pharmacological vocabulary for kinase drug discovery: one that asks not only whether a molecule inhibits its target kinase, but how ligand binding rewires protein stability, interactions, localisation, and function.

Chronic erythema nodosum leprosum (ENL) is a challenging complication of Hansen's disease (HD), with limited treatment options and frequent steroid dependence. Anti-tumour necrosis factor (TNF)-α agents are promising alternatives, though evidence remains confined to a few reports.

Patients with multiple myeloma receiving immunomodulatory drugs have an increased risk of venous thromboembolism (VTE), but the comparative effectiveness and safety of available prophylactic strategies remain uncertain. A systematic review and meta-analysis of randomized and prospective studies was conducted in accordance with PRISMA 2020. Studies evaluating aspirin, low-molecular-weight heparin (LMWH), warfarin, direct oral anticoagulants (DOACs), or no prophylaxis in patients receiving immunomodulatory therapy were included. Primary outcomes were symptomatic VTE and major bleeding. Twelve studies (n=2,435; 25 arm-level observations) were included. Descriptive pooled VTE incidence was 2.2% with apixaban, 5.1% with rivaroxaban, 5.6% with LMWH, 7.9% with aspirin, 9.1% with warfarin and 20.9% with no prophylaxis; these single-arm estimates are descriptive summaries of heterogeneous arms rather than adjusted between-class comparisons. LMWH significantly reduced VTE compared with warfarin, and aspirin reduced VTE compared with no prophylaxis. Major bleeding rates were low across active prophylaxis groups (0.3-1.6%). Evidence certainty was low or very low for every included study and very low for all DOAC evidence, reflecting small, heterogeneous and largely non-randomised studies. Active thromboprophylaxis is associated with substantially lower VTE incidence than no prophylaxis in patients with multiple myeloma receiving immunomodulatory therapy. Among established agents, LMWH has the most robust evidence base, though that base is itself of low certainty. Observations relating to DOACs, including apixaban, rest exclusively on very low certainty evidence from small prospective cohorts and feasibility studies and are strictly hypothesis-generating. Because the evidence is dominated by thalidomide-era regimens whereas contemporary therapy has evolved substantially, external validity to modern practice remains limited, and adequately powered randomised trials in current regimens are needed.

A man in his 20s presented with progressive fatigue and melena, with a history of recurrent epistaxis since adolescence and a positive family history. Evaluation revealed severe iron-deficiency anaemia (haemoglobin 27 g/L) with persistently positive faecal occult blood. Upper gastrointestinal endoscopy demonstrated multiple bleeding telangiectasias in the stomach and duodenum. Cross-sectional imaging of abdomen, thorax and brain identified multisystem arteriovenous malformations involving the liver, lung and brain. Despite repeated argon plasma coagulation and thalidomide therapy, bleeding persisted with ongoing transfusion dependence. Treatment with intravenous bevacizumab and subcutaneous octreotide stabilised haemoglobin and resolved occult gastrointestinal bleeding. A clinical diagnosis of hereditary haemorrhagic telangiectasia was established using Curaçao criteria despite negative genetic testing. This case highlights the importance of recognising hereditary haemorrhagic telangiectasia in unexplained severe anaemia and supports the role of anti-angiogenic therapy in refractory gastrointestinal bleeding.

Radiation-induced hemorrhagic gastroduodenitis is an intractable and potentially life-threatening condition. This study reports the case of a 57-year-old male with radiation-induced hemorrhagic gastroduodenitis. The patient had previously received radiotherapy for metastatic tumors involving the liver and adrenal gland. Following this treatment, he presented with melena and anemia, necessitating hospital admission. Prior therapeutic efforts included epinephrine spraying in the gastric antrum and embolization of the gastroduodenal artery. Despite these measures, along with multiple transfusions of packed red blood cells, the hemorrhage persisted. Ultimately, oral administration of thalidomide successfully controlled the bleeding. This case indicates that oral thalidomide may represent a potential treatment option for severe radiation-induced hemorrhagic gastroduodenitis.

This review covers published data (mostly from 2019 to 2025) on the synthesis and biological activity of azolo[a]quinoxalines, including pyrazolo-, imidazo- and triazolo-annelated systems. We highlight that most research efforts are directed toward the design of anticancer agents, with additional applications as Toll-like receptor antagonists, monoamine oxidase inhibitors, opioid receptor modulators, PI3Kα inhibitors, tubulin polymerization inhibitors, GABAᴀ receptor modulators, VEGFR-2 kinase inhibitors, BRD9 binders, and anti-inflammatory, antimicrobial, and antifungal agents. Recent synthetic strategies include Cu-catalyzed oxidative annulations, I2-mediated C-H functionalization, metal-free cascade cyclization, and multicomponent reactions, often employing eco-friendly catalysts and reductants. A growing number of studies integrate virtual screening, molecular docking, and pharmacophore-based in silico approaches to guide lead discovery and optimization. Innovative drug delivery systems, such as nanogels and hybrid molecules combining azoloquinoxalines with pharmacophores like thalidomide, have also been explored. This review emphasizes both the medicinal chemistry aspects of azolo[a]quinoxalines and the synthetic methodologies for their preparation from the perspective of drug development and discovery.