DVL1

Wingless/integrase-11 (WNT)/beta-catenin pathway is a crucial upstream regulator of a huge array of cellular functions. Its dysregulation is correlated to neoplastic cellular transition and cancer proliferation. Members of the Dishevelled (DVL) family of proteins play an important role in the transduction of WNT signaling by contacting its cognate receptor, Frizzled, via a shared PDZ domain. Thus, negative modulators of DVL1 are able to impair the binding to Frizzled receptors, turning off the aberrant activation of the WNT pathway and leading to anti-cancer activity.

Tubulin assembly

Drugs able to modulate the microtubule assembly either by inhibition of tubulin polymerization or by blocking microtubule disassembly are of great interest in anticancer therapy. Arylthioindoles (ATIs) bearing a 3-(3,4,5-trimethoxyphenyl)thio moiety have proven to be excellent tubulin polymerization inhibitors, with IC50s in the micromolar range. ATIs also inhibit MCF-7 cell growth at nanomolar concentrations, with potencies comparable to the reference compounds colchicine and combretastatin A-4

PDZ1 targeting NHERF1

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We reported novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents.

Beta-catenin

We identified a compound that abrogated the association between β-catenin and Tcf-4. The crystallographic analysis of the β-catenin Armadillo repeats domain revealed that the compound and Tcf-4 share a common binding site within the hotspot binding region close to Lys508. To our knowledge, it is the first small molecule ligand of this region to be reported. These results highlight the potential of this novel class of β-catenin inhibitors as anticancer agents

Carbonic anhydrase

Carbonic anhydrases are metal containing enzymes which catalyze the production of monohydrogen carbonate from carbon dioxide and water. We synthesized new pyrrole and indole derivatives as human carbonic anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/β-catenin signaling pathway (J Med Chem. 2023 Nov 9;66(21):14824-14842) The presence of both N1-(4-sulfonamidophenyl) and 3-(3,4,5-trimethoxyphenyl) substituents was essential for strong hCA inhibitors. The most potent hCA XII inhibitor 15 (Ki = 6.8 nM) suppressed the Wnt/β- catenin signaling pathway and its target genes MYC, Fgf20, and Sall4 and exhibited the typical markers of apoptosis, cleaved poly(ADP-ribose)polymerase, and cleaved caspase-3. Compound 15 showed strong inhibition of viability in a panel of cancer cells, including colorectal cancer and triple-negative breast cancer cells, was effective against the NCI/ADR-RES DOX-resistant cell line, and restored the sensitivity to doxorubicin (DOX) in HT29/DX and MDCK/P-gp cells. Compound 15 is a novel dual-targeting compound with activity against hCA and Wnt/β-catenin. It thus has a broad targeting spectrum and is an anticancer agent with specific potential in P-glycoprotein overexpressing cell lines.

CML

Chronic myelogenous leukemia (CML) is a clonal disease of hemopoietic progenitor cells. CML is characterized by the expression of the BCR-ABL fusion gene, which is derived from the fusion of the cellular breakpoint cluster region (BCR) gene and the Abelson murine leukemia oncogene (ABL). Imatinib is a potent inhibitor in all of the ABL tyrosine kinases, including BCR-ABL. Despite its initial efficacy, IM selects drug resistance due to the emergence of mutation at the kinase domain. PBTDs are a new class of agents with high apoptotic activity in K562 cells and in cells from patients at onset and who were imatinib-resistant. Our results demonstrated that PBTDs induce apoptosis in human BCR-ABL-expressing leukemia cells. The apoptotic activity was observed in primary leukemia blasts, obtained from CML patients at onset or from patients in blast crisis and who were IM-resistant.

Sars-CoV-2

SARS-CoV-2 was responsible for the recent COVID-19 pandemic, and HCoV-OC43 is the etiological agent of mild upper respiratory tract infections. SARS-COV-2 and HCoV-OC43 co-infections were found in children with respiratory symptoms during the COVID-19 pandemic. The two β-coronaviruses share a high degree of homology between the 3CLpro active sites, so much so that the safer HCoV-OC43 has been suggested as a tool for the identification of new anti-SARS-COV-2 agents. We identified compounds 5 and 24 that inhibited effectively both Wuhan and British SARS-CoV-2 patient isolates in Vero E6 cells and the HCoV-OC43 in MRC-5 cells at low micromolar concentrations (ACS Infectious Diseases, 2024). The inhibition was apparently exerted via targeting the 3CLpro active sites of both viruses. Compounds 5 and 24 at 100 μM inhibited the SARS-CoV-2 3CLpro activity of 61.78 and 67.30%, respectively. These findings highlight 5 and 24 as lead compounds of a novel class of antiviral agents with the potential to treat SARS-COV-2 and HCoV-OC43 infections.

HIV-1

The search for anti-AIDS agents led to the development of potent classes of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs): PBTD, PAS and IAS. The potent activity of IASs against the NNRTI-resistant mutants correlated to the presence of a 3-(3,5-dimethylphenyl)sulfonyl moiety. Potent IAS derivatives were also obtained by adding to the 2-carboxyamide nitrogen natural and unnatural amino acid units to give derivatives with activity against HIV-1 WT and NNRTI-resistant mutants superior to that of the parent indole derivative L-737,126.

Zika

Zika virus (ZIKV) infection which initially was endemic only in Africa and Asia, is rapidly spreading throughout Europe, Oceania, and the Americas. Although enormous efforts, there is still no approved drug to treat ZIKV infection. We reported the synthesis and biological evaluation of agents with non-competitive mechanism of the ZIKV NS2B/NS3 protease inhibition through the binding to an allosteric site. Two compounds showed potent activity in both enzymatic and cellular assays. The most active compound efficiently reduced the ZIKV protein synthesis and the RNA replication, and prevented the mice from life-threatening infection and the brain damage caused by ZIKV infection in a ZIKV mouse model.

Dengue

Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. We identified new compounds with anti-DENV targeting RdRp and NS3 protease, using cell-based reporter assay. These compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication