Amit Shard

2,5-Diazabicyclo[2.2.1]heptane (2,5-DBH) is a conformationally rigid bicyclic diamine and a privileged scaffold in medicinal chemistry, enabling diverse synthetic modifications and broad therapeutic applications across multiple disease areas.

Pyruvate kinase M2 (PKM2) is a central regulator of glycolysis and anabolic metabolism, playing a pivotal role in cancer cell proliferation. Its multifunctional nature and involvement in various disease pathways make it an attractive therapeutic target, especially in oncology and inflammation. This review summarizes research over the past five years on small molecule PKM2 inhibitors. Activators of PKM2 promote the tetrameric form of PKM2, enhancing oxidative phosphorylation and reversing the Warburg effect. In contrast, inhibitors like micheliolide (MCL) and isoselenazolium compounds disrupt PKM2's non-metabolic roles, inducing tumor cell death. Literature was selected through focused searches on PKM2-targeted therapies in cancer, inflammation, and neurodegeneration, with attention to recent advances in structural biology, computational modeling, and high-throughput screening. PKM2 modulators show promise across a range of diseases beyond cancer, including inflammatory and neurodegenerative conditions. However, challenges in isoform selectivity, toxicity, and clinical translation persist. Although, no PKM2 inhibitors have entered and succeeded in clinical trials, continued research and technological advances are essential to unlock PKM2's full therapeutic potential and guide its development into safe, effective clinical treatments.

Colorectal cancer (CRC) remains a major global health burden, with current treatments primarily focused on eradicating cancer cells. However, chemotherapy-induced gut dysbiosis exacerbates inflammation and disease progression, necessitating innovative therapeutic strategies. While various metabolic inhibitors and microbiome-modulating approaches have been explored separately, no reported agent to date simultaneously targets both cancer cell survival and gut microbiome restoration. We designed thiazole-based pyruvate kinase M2 (PKM2) inhibitors, hypothesizing that selective modulation may suppress tumor growth while restoring gut microbial balance. 10j selectively inhibited PKM2 in a cell-free assay (0.01 ± 0.0009 μM) and in CRC cells (4.21 ± 0.04 μM), disrupting key pathways driving CRC progression. Remarkably, metagenomic analysis revealed that 10j restored gut microbiota balance. These findings suggest that dual-function anticancer agents, which kill cancer cells while simultaneously restoring gut microbiota, represent an unexplored therapeutic avenue. Thiazole-based PKM2 inhibitors are pioneering this novel strategy in CRC treatment.

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. Methods We administered three different dosages of ChABC (0.0001U, 0.00025U, and 0.0005U) in the coccygeal disc. Subsequently, the model was validated through behavioural tests (tail flick and von Frey). Additionally, a comprehensive morphological evaluation of the disc was assessed using H&E, MT, and SO-FG staining. Also, various IHC markers like Collagen-I, II, Aggrecan, and SOX-9 expressions were analyzed. Results Administration of a 0.00025U dose of ChABC at day 28 led to a significant upregulation of PKM2, TSK, IL-1β, and cellular hypertrophy, all hallmarks of IVDD. The onset of IVDD was associated with a decrease in collagen-II, Aggrecan, and markers of chondrogenesis, contributing to increased pain, inflammation, and tissue disorganization. Notably, selective inhibition of PKM2 using IMID-284 resulted in reduced pain and inflammation, alongside a protective effect on cartilage, suggesting that PKM2 plays a pivotal role in IVDD pathophysiology. Conclusion These findings indicate that PKM2 inhibition may represent a promising therapeutic strategy for mitigating the biochemical and structural changes underlying disc degeneration. Overall, the study provides new insights into how PKM2 inhibition could arrest the progression of IVDD, pain, and inflammation.

This study investigates the pharmacokinetic, physicochemical, and metabolite properties of 9b , a novel imidazopyrimidine‐based sulfonamide previously shown to be effective against the A549 lung adenocarcinoma cell line. Aiming to evaluate its ADME (absorption, distribution, metabolism, and excretion) characteristics for drug development, the study found that 9b possesses favorable physicochemical properties, including a pKa of 12.35, LogP of 2.89, and LogD of 0.98. Stability tests demonstrated that 9b remains stable in human plasma and liver microsomes for up to 1 h, with moderate plasma protein binding (46%). Metabolite profiling using LC/Q‐TOF MS revealed three major metabolites ( M1 , M2 , and M3 ), whereas in vivo pharmacokinetic analysis via LC/QQQ‐MS indicated optimal pharmacokinetic parameters, including C _max , T _max , AUC, and a half‐life (t _1/2 ) consistent with a balanced pharmacokinetic profile. These results highlight 9b ’s promising stability, moderate protein binding, and favorable metabolic profile, positioning it as a strong candidate for further development as an anticancer drug. Given its impressive pharmacokinetic properties and demonstrated efficacy in cancer cell lines, 9b shows significant potential for advancing cancer treatment.