benzosuberene / Oncotelic - LARVOL DELTA

Targeting Tumor-Associated Hypoxia with Bioreductively Activatable Prodrug Conjugates Derived from Dihydronaphthalene, Benzosuberene, and Indole-based Inhibitors of Tubulin Polymerization. (PubMed, RSC Med Chem) - "Structure activity relationship-guided studies in our laboratories led to the discovery of promising lead molecules (OXi6196, KGP05, KGP18, and OXi8006) that bind to the colchicine site on the tubulin heterodimer. Biological evaluation against the A549 human lung carcinoma cell line (under normoxic versus anoxic conditions) revealed several BAPCs with positive hypoxia cytotoxicity ratios. Preliminary in vivo evaluation of a representative BAPC (KGP291) demonstrated vascular shutdown in nude mice bearing orthotopic 4T1 breast tumors studied by bioluminescence imaging."

Journal • Breast Cancer • Lung Cancer • Oncology • Solid Tumor

Benzosuberene and Tetracyclic Analogues as Colchicine Site Inhibitors of Tubulin Polymerization. (PubMed, ACS Med Chem Lett) - "In a preliminary study of VDA efficacy, these prodrugs caused blood flow disruption in mice, as revealed by bioluminescence imaging with histological confirmation. The most effective analogues from this series offer promise as cancer therapeutic agents."

Journal • Oncology

Evaluation of Pyrrolone-Fused Benzosuberene MK2 Inhibitors as Promising Therapeutic Agents for HNSCC: In Vitro Efficacy, In-Vivo Safety, and Pharmacokinetic Profiling. (PubMed, Drug Dev Res) - "Pharmacokinetic studies showed that PfBS analogues exhibited rapid absorption (Tmax), adequate plasma concentration above the micromolar level (C0 or Cmax), limited tissue distribution (Vd), and faster elimination from the body (Cl). Overall, this study summarizes in-vitro efficacy, safety, and pharmacokinetics of developed MK2-inhibitors and opens doors for pharmacodynamics and mechanism of action study of most effective leads in HNSCC."

Journal • PK/PD data • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MAPKAPK2

Pd-Catalyzed Tandem Approach for 1,2,3-Triazolo-azepine Fused Benzosuberenes and 1,2,3-Triazolobenzazepines Synthesis. (PubMed, J Org Chem) - "Furthermore, computational studies were also performed to validate the proposed mechanistic pathways. Additionally, the developed protocol is applicable to the gram-scale synthesis of TAABS analogues."

Journal

Novel pyrrolone-fused benzosuberene MK2 inhibitors: synthesis, pharmacophore modelling, molecular docking, and anti-cancer efficacy evaluation in HNSCC cells. (PubMed, J Biomol Struct Dyn) - "Moreover, immunofluorescence analysis and western-blot assays potentiated, that selected analogues inhibited the inflammatory cytokine TNF-α induced activation of MK2 on cellular and molecular levels in HNSCC cells. In conclusion, this study presents novel MK2-inhibitors and opens the avenue for further pre-clinical and clinical efficacy evaluation of developed PfBS analogues in the treatment of HNSCC.Communicated by Ramaswamy H. Sarma."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MAPKAPK2 • TNFA

Application of Chlorosulfonyl Isocyanate (CSI) in the Synthesis of Fused Tetracyclic Ketone Ring Systems. (PubMed, J Org Chem) - "A serendipitous discovery of the pertinence of CSI occurred during a structure-activity relationship campaign around our established lead benzosuberene-based molecule that functions as a potent inhibitor of tubulin polymerization...Notably, simplified arene structures with fewer substituents were also observed to undergo cyclization under these conditions. This strategy represents a promising approach for the synthesis of appropriately functionalized tetracyclic ring systems."

Journal

Synthesis and biological evaluation of cathepsin B cleavable drug-linker constructs featuring modified spacers with novel phenolic payload KGP18 | Poster Board #942 (ACS-Sp 2024) - "Adcetris®, a cathepsin B cleavable Val-Cit dipeptide drug linker, features monomethyl auristatin E (MMAE), an inhibitor of tubulin polymerization, as its payload...One highly active phenolic-based benzosuberene payload, KGP18, demonstrated potent inhibition of tubulin polymerization and antiproliferative activity (GI 50 values low nM/pM) against a variety of human cancer cell lines...The overall goal is to identify synthetically accessible drug-linker constructs suitable for the incorporation of phenolic-based payloads, which undergo efficient enzyme-mediated cleavage. In a related study, a Val-Ala dipeptide bearing a direct phenolic-linkage of KGP18, similar to the FDA approved ADC Zynlonta®, was synthesized to allow comparison to other dipeptide linkers in cleavage studies."

Oncology • CTSB

Bioreductively activatable prodrug constructs for hypoxia selective delivery of dual-mechanism inhibitors of tubulin polymerization | Poster Board #946 (ACS-Sp 2024) - "These molecules, which include benzosuberene, dihydronaphthalene, and indole analogues as representative examples, demonstrate stronginhibition of tubulin polymerization (colchicine site) andfunction through a unique dual-mechanism of action as potent antiproliferative agents and promising tumor-selective vascular disrupting agents (VDAs). Current efforts directed towards the synthesis and biological evaluation of bis-prodrug constructs designed for hypoxia-selectivity along with enhanced aqueous solubility will be described. These efforts include the incorporating of amino acids at the indole nitrogen as well as optimization of a challenging Mitsunobu reaction to install hypoxia-selective triggers."

Lung Cancer • Oncology • Solid Tumor

Design and synthesis of drug-linker constructs to optimize incorporation of phenolic-based payloads for potential application in cancer therapeutics through antibody-drug conjugate (ADC) technology | Poster Board #940 (ACS-Sp 2024) - "KGP660 was synthesized which tethers a phenolic benzosuberene-based payload directly to the PAB spacer, and this construct demonstrated improved release (61% by cat B over 24 h) compared to KGP474 with the DMED spacer. Synthetic efforts towards new drug-linker constructs incorporating phenolic bearing payloads, such as KGP660, and a construct incorporating a methylene alkoxy carbamate spacer are described."

Oncology • CTSB

Targeting anticancer agents to the tumor microenvironment with cathepsin B cleavable drug-linker conjugates of phosphatidylserine-binding proteins (AACR 2023) - "The payloads include benzosuberene-based aniline KGP156 and its phenolic congener KGP18, dihydronaphthalene-based KGP05, and indole-based OXi8006. Conjugation of thiolated Bavituximab with Mc-Val-Cit-PABC-KGP156 gave a drug/antibody ratio (DAR) of 3.6/1 after cleavage by cathepsin B and determination of released KGP156 by LC-MS. These studies revealed 1) distinct differences in cleavage rates for drug-linkers, 2) cleavage by cathepsin L, and 3) efficient cathepsin B mediated release of payload from the ADC."

Biomarker • Tumor microenvironment • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CTSB

Synthesis of benzosuberene-based analogues inspired by natural products: Their action as inhibitors of tubulin polymerization as potential anti-cancer agents (ACS-Sp 2023) - "The colchicine site located primarily on the beta-subunit of the tubulin heterodimer, remains a promising target for highly effective and selective small-molecule inhibitors designed to function as therapeutic agents for the treatment of cancer. The promising activity of KGP521 inspired further exploration of related benzosuberene analogues through conversion to their corresponding tetracyclic compounds upon reaction with CSI. Further details regarding the design and synthesis of these novel tetracyclic analogues along with their preliminary biological evaluation will be presented."

Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Synthesis of drug-linker constructs bearing dual mechanism of action payloads designed for cleavage by enzymes present in the tumor microenvironment (ACS-Sp 2023) - "The natural products colchicine and combretastatin A-4 (CA4) inspired significant world-wide drug discovery efforts targeting the colchicine binding site, which is located primarily on the beta-tubulin heterodimer...Two highly potent, benzosuberene-based, dual-mechanism payloads, KGP18 and KGP156, were tethered through protease-cleavable short peptides to afford corresponding drug-linker constructs that also incorporate a self-immolative para-aminobenzyl trigger to facilitate release of the payloads...Studies utilizing unique engineered proteins (referred to as betabodies), advanced by the Brekken Laboratory, that selectively target accessible phosphatidylserine (PS) will also be described. Though confined to the inner leaflet of the plasma membrane of healthy cells, PS is exposed on the outer leaflet of the plasma membrane of endothelial cells in tumor-associated vasculature and cancer cells, thus representing a promising target for these unique drug-linker constructs."

Biomarker • Tumor microenvironment • Oncology

Identification of 11β-HSD1 inhibitors through enhanced sampling methods. (PubMed, Chem Commun (Camb)) - "Aminoarylbenzosuberene (AAB) molecules were chosen for in silico analysis to develop effective and more competent 11β-hydroxysteroid dehydrogenase (11β-HSD1) protein inhibitors. The AAB4 molecule was shown to have stronger interactions and binding affinity than standard inhibitors (co-crystallized molecules). These results were based on conventional, steered and enhanced umbrella sampling simulations."

Journal

Synthesis of Benzosuberene-based Compounds Designed to Function as Inhibitors of Tubulin Polymerization and Development of Drug Linker Constructs for Selective Targeting (ACS-Sp 2022) - "In preliminary studies, these small-molecule benzosuberene payloads were synthetically linked to dipeptide sequences terminating in a maleimido caproic acid moiety and evaluated in protease cleavage studies. Cleavable linker constructs that incorporate aniline-based payloads and the valine-citruline dipeptide (widely used in drug-linker constructs) were efficiently cleaved by cathepsin B and cathepsin L. The drug linker construct integrating the KGP156 payload demonstrated an average release (over 3 experiments) of the payload upon enzyme exposure (90 minutes) from NAC-Mc-Val-Cit-PABC-KGP156: 98% (cathepsin B); 95% (cathepsin L)."

Breast Cancer • Oncology • Solid Tumor • CTSB • CTSL

Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment. (PubMed, Cancers (Basel)) - "The selective disruption of tumor-associated vasculature represents an attractive therapeutic approach. A combination with carboplatin produced significantly greater tumor growth delay than carboplatin alone, though significant carboplatin-associated toxicity was observed (whole-body weight loss). KGP265 was found to be effective at low concentrations, generating long-term vascular shutdown and tumor growth delay, thus providing strong rationale for further development, particularly in combination therapies."

Journal • Breast Cancer • Genito-urinary Cancer • Hematological Disorders • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Plant-based analogues identified as potential inhibitor against tobacco mosaic virus: A biosimulation approach. (PubMed, Pestic Biochem Physiol) - "Benzosuberene compounds with a pyrrolone group adhered to it are compounds extracted from the oils of Cedrus deodara plant, that bear inhibitory capabilities...Our investigation proved that the reported ligands (ligands 3, 7, 9, and 17 obtained -177.103, -228.632, -184.134, and - 188.075 kJ/mol binding energies, respectively) interacted with the binding site of TMV much efficiently than the known inhibitors (Ribavirin and Zhao et al...Moreover, they acquired a stable conformation inside the binding pocket, where a higher number of binding site residues contributed towards interaction. Thus, their structural framework can be optimized for the exploration of their antiviral properties to develop potent botanical viricides against plant virus infection."

Journal • Infectious Disease

Benzosuberene-sulfone analogues synthesis from Cedrus deodara oil and their therapeutic evaluation by computational analysis to treat type 2 diabetes. (PubMed, Bioorg Chem) - "Benzosuberene-sulfone (BSS) analogues have been semi-synthesized following green approaches from himachalenes, which has been extracted from essential oil of Cedrus deodara. Our computational studies suggested that the molecule 3q performed better than the standard drug (Rosiglitazone) in all three protein structures. This implies that our suggested molecule could act as a more potent antagonist to native PPARG and could also be developed to treat type-2 diabetes patients with R357A and V290M mutations, which didn't elicit any response to currently available drugs in the market."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • PPARG

[VIRTUAL] Ni-catalyzed alkene dialkylation via coordination-assisted metallacycles (ACS-Sp 2021) - "The reaction is assisted by imine-coordination and proceeds with the catalytic turnover number (TON) and turnover frequency (TOF) up to 2 × 103 and 165 h–1 at room temperature, respectively. This dialkylation reaction generates products with three contiguous all-carbon stereocenters, which can be readily elaborated to complex tetralene, benzosuberene, and bicyclodecene structures."

Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration. (PubMed, J Biomol Struct Dyn) - "In this study, we have chosen Flavopiridol, SU9516, and CVT-313 as standard inhibitors to compare with in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds. These outcomes led towards positioning a potential natural molecule as selective inhibitor for CDK2 with low side effects. Communicated by Ramaswamy H. Sarma."

Journal • Oncology • CDK1 • CDK2 • CDK9

Ni-Catalyzed Regioselective 1,2-Dialkylation of Alkenes Enabled by the Formation of Two C(sp)-C(sp) Bonds. (PubMed, J Am Chem Soc) - "The products can be readily elaborated to access complex tetralene, benzosuberene, and bicyclodecene cores. The reaction also features as the most efficient alkene difunctionalization process to date with catalyst loadings down to 500 ppm and the catalytic turnover number (TON) and turnover frequency (TOF) registering up to 2 × 10 and 165 h at rt, respectively."

Journal

Target identification, screening and in vivo evaluation of pyrrolone-fused benzosuberene compounds against human epilepsy using Zebrafish model of pentylenetetrazol-induced seizures. (PubMed, Sci Rep) - "Additionally, gene expression studies performed for the genes of the PI3K/AKT/mTOR pathway which further validated our results. In conclusion, these findings suggested that PBS-8 is a promising candidate that could bedeveloped as a potential antiepileptic."

Journal • CNS Disorders • Epilepsy

Discovery and in silico evaluation of aminoarylbenzosuberene molecules as novel checkpoint kinase 1 inhibitor determinants. (PubMed, Genomics) - "The computational strategy indicates that the Bch10 could be regarded as a potential CHK1 inhibitor in comparison with top five co-crystallize molecules. Bch10 signifies a promising outlet for the development of potent inhibitors for CHK1."

Journal • Oncology • CHEK1

Structure Guided Design, Synthesis, and Biological Evaluation of Novel Benzosuberene Analogues as Inhibitors of Tubulin Polymerization. (PubMed, J Med Chem) - "A promising design paradigm for small-molecule inhibitors of tubulin polymerization that bind to the colchicine site draws structural inspiration from the natural products colchicine and combretastatin A-4 (CA4). Ten new molecules were effective inhibitors of tubulin polymerization (IC < 5 µM) with seven of these exhibiting highly potent activity comparable to CA4, KGP18, and KGP03. For one of the most effective agents, dose-dependent vascular shutdown was demonstrated using dynamic bioluminescence imaging in a human prostate tumor xenograft growing in a rat."

Journal • Oncology • Prostate Cancer

Structural based study to identify new potential inhibitors for dual specificity tyrosine-phosphorylation- regulated kinase. (PubMed, Comput Methods Programs Biomed) - "Methods The library of in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds was docked with DYRK1A receptor...Conclusion The stated methodologies revealed a unique mechanism of active site binding. The binding interactions within the active site showed that the chosen molecules had notable interactions than the standard molecule, which led to the generation of potential compounds to inhibit DYRK1A."

Journal

Natural analogues inhibiting selective Cyclin-dependent kinase protein isoforms: A computational prospective. (PubMed, J Biomol Struct Dyn) - "Based on our molecular docking results, Ligands-3, 5, 14, and 16 were screened among 17 different Pyrrolone-fused benzosuberene (PBS) compounds as potent and specific inhibitors without any cross-reactivity against different CDK isoforms...These ligands are expected to possess lower risk of side effects due to their natural origin. Moreover, the backbone structure of these ligands could also be exploited to develop specific inhibitors against other CDK isoforms."

Clinical • Journal • CDK2