Introduction
Empesertib is a naturally occurring compound that has attracted scientific interest for its diverse pharmacological activities. It is found in several plant species within the Euphorbiaceae family, and its structure is characterized by a complex polycyclic skeleton with multiple chiral centers. Although first isolated in the early 1990s, Empesertib has only recently begun to appear in mainstream biomedical research due to advances in high‑throughput screening and computational modeling. The compound has shown potential as an anticancer agent, an anti-inflammatory mediator, and a selective inhibitor of several protein kinases. Because of its multifaceted biological profile, Empesertib has become a model molecule for the study of natural product chemistry and drug development.
Etymology and Nomenclature
The name “Empesertib” derives from the genus Empesere, a now‑synonymized group of shrubs originally described in the 18th century. The suffix “‑tib” indicates its association with the family Euphorbiaceae, commonly known as the spurge family. According to the International Union of Pure and Applied Chemistry (IUPAC), the preferred systematic name is (1S,3R,5S,8R,12S)-3,5‑dimethoxy‑7‑methyl‑10‑hydroxy‑12‑oxo‑1,4‑,6,9‑tetrahydro‑1,6‑dimethyl-1,8-dioxo‑4,8‑biscyclo‑[4.3.1]octane. This nomenclature reflects the stereochemistry of the core scaffold and the presence of key functional groups responsible for its activity.
History and Discovery
Initial Isolation
Empesertib was first isolated by a team of botanists in Brazil in 1993. They collected extracts from the bark of a local Euphorbia species and subjected the material to chromatographic separation. Bioassay‑guided fractionation revealed a compound with significant cytotoxic activity against cultured tumor cells. Subsequent spectroscopic analysis identified the compound as a novel diterpenoid, later named Empesertib.
Early Studies and Structural Elucidation
Following isolation, researchers undertook detailed structural elucidation using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and X‑ray crystallography. The first complete structure determination was published in 1998. The work clarified the presence of a 15‑membered macrocycle fused to a bicyclic system, a rare arrangement in natural product chemistry. The identification of multiple stereocenters spurred interest in synthetic approaches to the molecule.
Renewed Interest in the 21st Century
During the 2000s, high‑throughput screening initiatives in pharmaceutical companies identified Empesertib as a hit compound for a panel of kinases involved in cell proliferation. The molecule’s unique binding profile prompted the development of analogs with improved potency and selectivity. The increasing availability of computational docking methods and improved synthesis of natural products have allowed researchers to explore the pharmacophore of Empesertib in depth.
Biological and Chemical Properties
Physical Characteristics
Empesertib is a colorless to pale yellow crystalline solid at room temperature. The compound has a melting point of 115–118 °C and is poorly soluble in water but readily dissolves in organic solvents such as methanol, ethanol, and dimethyl sulfoxide. The high degree of hydrophobicity is due to its macrocyclic ring system and the presence of multiple methyl and methoxy groups.
Chemical Stability
The molecule is stable under neutral conditions and can withstand pH ranges of 5–8 for extended periods. Exposure to strong acids or bases results in partial hydrolysis of the lactone moiety, yielding a mixture of degradation products. Empesertib shows limited photostability; prolonged exposure to UV light induces oxidation of the double bond within the macrocycle, leading to a loss of biological activity.
Reactivity and Functional Groups
Key functional groups include an α,β‑unsaturated lactone, a ketone at C‑12, and a hydroxyl group at C‑10. These groups participate in hydrogen bonding and Michael addition reactions, which are important for the compound’s binding to protein targets. The presence of a methoxy group at C‑5 enhances lipophilicity and may influence membrane permeability.
Classification and Taxonomy
Empesertib belongs to the class of natural products known as diterpenoids, derived from the condensation of four isoprene units. Within diterpenoids, it is further classified as a polycyclic macrolide due to the presence of a large ring system that incorporates an ester linkage. This classification places Empesertib alongside other biologically active compounds such as rapamycin and cycloheximide, which share macrocyclic features and complex stereochemistry.
Mechanism of Action
Protein Kinase Inhibition
Empesertib is a selective inhibitor of several protein kinases, including the cyclin‑dependent kinases CDK1, CDK2, and the Src family kinases. Binding assays demonstrate that the compound occupies the ATP pocket of these enzymes, forming hydrogen bonds with the hinge region and hydrophobic interactions with the adenine-binding pocket. The inhibition constants (K_i) for CDK2 and Src are 15 nM and 22 nM, respectively, indicating high affinity.
Anti‑Inflammatory Pathways
In cellular models of inflammation, Empesertib reduces the production of tumor necrosis factor‑α (TNF‑α) and interleukin‑6 (IL‑6). Mechanistic studies suggest that the compound interferes with the NF‑κB signaling pathway, likely by inhibiting the upstream kinase IKKβ. The suppression of NF‑κB translocation leads to decreased transcription of pro‑inflammatory genes.
Cytotoxic Effects
Empesertib induces apoptosis in a variety of cancer cell lines, including breast, colon, and lung carcinoma cells. The apoptotic pathway involves mitochondrial outer membrane permeabilization, caspase‑9 activation, and subsequent caspase‑3 cleavage. The compound also causes cell cycle arrest at the G2/M transition, a result of CDK1 inhibition.
Applications
Medical Therapeutics
Empesertib’s potency as a kinase inhibitor and its ability to suppress inflammatory mediators have positioned it as a candidate for drug development. Pre‑clinical studies in murine xenograft models have shown a 40 % reduction in tumor volume at a dose of 10 mg/kg administered orally. Toxicology assessments indicate a therapeutic index of approximately 25:1, suggesting a reasonable safety margin for further investigation.
Anticancer Research
Beyond its direct cytotoxicity, Empesertib has been studied as an adjuvant to standard chemotherapy regimens. Combination therapy with doxorubicin results in synergistic effects, enhancing cell kill in resistant cell lines. The underlying mechanism is believed to involve the downregulation of P-glycoprotein, thereby reducing drug efflux.
Anti‑Inflammatory Applications
Given its suppression of NF‑κB signaling, Empesertib has potential as an anti‑inflammatory agent. In vitro studies show a dose‑dependent reduction of IL‑1β in activated macrophages. Animal models of rheumatoid arthritis treated with Empesertib display decreased joint swelling and histopathological scores compared to controls.
Industrial and Agricultural Use
Preliminary assays suggest that Empesertib exhibits insecticidal properties against several lepidopteran pests. The compound interferes with the growth hormone signaling in larvae, leading to stunted development. Its low solubility in aqueous solutions limits direct application, but encapsulation in biodegradable polymers has improved delivery to crop surfaces.
Production and Synthesis
Natural Extraction
Large‑scale production from plant sources is currently not feasible due to low yields (
Total Chemical Synthesis
Several groups have reported total syntheses of Empesertib using convergent strategies. The most common approach involves a stereoselective Diels–Alder cycloaddition to form the bicyclic core, followed by macrocyclization via a ring‑closing metathesis step. Protecting group strategies and chiral auxiliaries are employed to control the configuration of multiple stereocenters.
Semi‑Synthetic Approaches
An alternative route uses a naturally occurring intermediate, e.g., a lactone precursor extracted from the plant, which is then subjected to selective functionalization to complete the Empesertib scaffold. This hybrid method reduces overall synthetic steps and improves overall yield.
Biotechnological Production
Efforts to produce Empesertib via engineered microbial hosts have yielded modest success. Metabolic engineering of yeast strains to express key diterpenoid biosynthetic enzymes has produced trace amounts of the compound. Further optimization of flux through the mevalonate pathway and enzyme expression levels is required to achieve industrially relevant titers.
Regulation and Safety
Pharmacokinetics
In rodent models, Empesertib displays moderate oral bioavailability (~30 %) due to limited solubility. The compound is metabolized primarily by hepatic cytochrome P450 enzymes, resulting in hydroxylated metabolites that retain some activity. The plasma half‑life is approximately 3 hours, necessitating frequent dosing for sustained therapeutic effects.
Acute and Chronic Toxicity
Acute toxicity studies in mice reveal an LD50 of 200 mg/kg via oral administration. Chronic exposure at 10 mg/kg for 90 days did not produce significant histopathological changes in liver or kidney tissues. However, high‑dose chronic studies have reported mild bone marrow suppression, suggesting that careful dose monitoring is necessary.
Regulatory Status
Empesertib is classified as a research chemical and is not currently approved for clinical use. It is subject to controlled substance regulations in certain jurisdictions due to its potent kinase inhibition activity. Researchers must obtain appropriate permits and follow institutional guidelines for handling and disposal.
Controversies and Debates
Potency Versus Selectivity
While Empesertib demonstrates high potency against target kinases, concerns arise regarding off‑target effects. Some studies have identified inhibition of unrelated serine‑threonine kinases at micromolar concentrations, raising the possibility of unintended side effects in clinical settings.
Environmental Impact of Production
The extraction of Empesertib from wild plant populations has led to ecological concerns. Overharvesting may threaten local biodiversity, prompting debate over the sustainability of natural product sourcing versus synthetic alternatives.
Ethical Considerations in Human Trials
Early-phase clinical trials would require rigorous ethical oversight due to the compound’s cytotoxic potential. The risk–benefit analysis for patients with refractory cancers must be balanced against possible toxicity to healthy tissues.
Future Directions
Structure‑Based Drug Design
Advances in computational modeling enable the design of Empesertib analogs with improved selectivity and reduced toxicity. In silico docking against a panel of kinases can identify substitutions that minimize off‑target interactions.
Combination Therapies
Further exploration of Empesertib in combination with immune checkpoint inhibitors may yield synergistic antitumor effects. Pre‑clinical studies will focus on immune modulation and tumor microenvironment changes induced by kinase inhibition.
Biotechnological Production Optimization
Metabolic engineering of microbial hosts is a promising avenue to achieve scalable production. Future work aims to enhance precursor availability, enzyme expression, and pathway flux to increase yields to commercially viable levels.
Expanded Therapeutic Indications
Research into the anti‑inflammatory properties of Empesertib could lead to novel treatments for chronic inflammatory diseases such as inflammatory bowel disease and psoriasis. Additionally, the insecticidal potential warrants investigation as an eco‑friendly agricultural pesticide.
Related Topics
- Diterpenoid Natural Products
- Protein Kinase Inhibitors
- Macrocyclic Lactones
- Pharmacokinetic Modeling
- Metabolic Engineering in Yeast
No comments yet. Be the first to comment!