European Journal of Medicinal Chemistry

Current progress and novel strategies that target CDK12 for drug discovery

CDK12 is a cyclin-dependent kinase that plays critical roles in DNA replication, transcription, mRNA splicing, and DNA damage repair. CDK12 genomic changes, including mutation, amplification, deletion, and fusion, lead to various cancers, such as colorectal cancer, gastric cancer, and ovarian cancer. An increasing number of CDK12 inhibitors have been reported since CDK12 was identified as a biomarker and cancer therapeutic target. A major challenge lies in that CDK12 and CDK13 share highly similar sequences, which leads to great difficulties in the development of highly selective CDK12 inhibitors. In recent years, great efforts were made in developing selective CDK12 blockers. Techniques including PROTAC and molecular glue degraders were also applied to facilitate their development. Also, the drug combination strategy of CDK12 small molecule inhibitors were studied. This review discusses the latest studies on CDK12 inhibitors and analyzes their structure-activity relationships, shedding light on their further development.

Novel Hsp90-Targeting PROTACs: Enhanced synergy with cisplatin in combination therapy of cervical cancer

The development of effective drugs for cervical cancer is urgently required because of its high mortality rate and the limited treatment options. Herein, we report the design, synthesis, and evaluation of a series of novel and effective Hsp90-targeting PROTACs. These compounds exhibited potent anti-proliferative activity against cervical cancer cells with low IC

Design, synthesis and biological evaluation of seco-DSP/DCK derivatives reversing P-glycoprotein-mediated paclitaxel resistance in A2780/T cells

P-glycoprotein transporter (P-gp, ABCB1) is a major contributor to multidrug resistance, making it a valuable target for the development of novel P-gp inhibitor to overcome multidrug resistance. In this study, forty-nine novel seco-DSPs and seco-DMDCK derivatives were synthesized and evaluated their chemo-sensitize abilities to paclitaxel in A2780/T cell lines. Most of them exhibited a comparable reversal multidrug-resistance activity than verapamil. Especially, compound 27f showed a remarkable chemo-sensitization with more than 425-fold reversal ratio in A2780/T cells. The study of preliminary pharmacological mechanism displayed that compound 27f was more effective to increase the accumulation of paclitaxel and Rhodamine 123 than verapamil via inhibiting P-gp for reversing multidrug-resistance. In addition, a higher than 40 μM IC

Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers

An increasing number of artemisinin (ARS) and its derivatives have been reported for their potential therapeutic value of human cancer. However, their therapeutic potencies are limited owing to their poor pharmacokinetic profiles. Our previous studies showed that a lead compound ARS4 originated from incorporating the pharmacophore of the approved chemotherapeutic agent melphalan into the basic skeleton of artemisinin with a succinic linker exhibited an excellent toxicity to human ovarian cancer cells and low cytotoxicity to normal cells. The mechanism studies demonstrated that it inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis and inhibition of migration. Meanwhile, it exhibited excellent antitumor activities in animal models. Herein, further structure optimization for this lead compound ARS4 was performed and nineteen novel derivatives were designed and synthesized. Among them, compounds 10-12, 15, 16, 18 and 19 demonstrated powerful cytotoxic effects against human liver cancer and ovarian cancer cell lines, with their IC

Discovery of novel 7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines as ATR inhibitors based on structure-based drug design

ATR kinase is essential to the viability of replicating cells responding to the accumulation of single-strand breaks in DNA, which is an attractive anticancer drug target based on synthetic lethality. Herein we design, synthesize, and evaluate a novel series of fused pyrimidine derivatives as ATR inhibitors. As a result, compound 48f, with an IC

The novel SIRT2-targeted PROTAC degraders as the efficient agents for the treatment of ovarian cancer

Ovarian cancer is a highly lethal gynecological malignancy that poses a significant threat to women's health. Current treatments for patients with clinical recurrence and drug resistance are limited, underscoring the urgent need for new therapeutic strategies. SIRT2, one subtype of sirtuin protein family, has been shown to promote tumor cell proliferation, migration, and invasion by regulating multiple signaling pathways through deacetylation. In this study, we discovered that knockdown of SIRT2 significantly inhibited the migration and invasion of ovarian cancer cells. To develop targeted therapies, we designed and synthesized a series of SIRT2-targeted PROTACs based on the small molecule inhibitor Tenovin-6. These PROTACs exhibited potent SIRT2 degradation capability and significant anti-proliferative activity in several ovarian cancer cell lines. Among them, W10 demonstrated the most potent anti-proliferative activity both in vitro and in vivo, with an IC

Synthesis and in vitro and in vivo evaluation of novel bivalent quinolines as antitumor agents via targeting autophagy in cervical cancer

A series of novel bivalent quinolines with a spacer of four to six methylene units between the phenoxy group in the position-7 and various substituents in the position-4 of quinoline skeleton, respectively, were synthesized and evaluated as anticancer agents. The data showed that the majority of the compounds had significant antiproliferative activity with IC

Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma

Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Moreover, TP sequence has a high affinity with plasmin, a protease recognized as overexpressed in many solid cancers, including HCC and ovarian carcinoma. The prodrugs were synthesized and fully characterized in terms of in vitro ADME properties, plasma stability and plasmin-induced release of the parent drug. The inhibitory activity against Sgk1 was evaluated and in vitro growth inhibition was evaluated on ovarian carcinoma and HCC cell lines in the presence and absence of human plasmin. In vivo pharmacokinetic properties and preliminary tissue distribution confirmed a better profile highlighting the importance of the prodrug approach. Finally, the prodrug antitumor efficacy was evaluated in an HCC xenografted murine model, where a significant reduction (around 90%) in tumor growth was observed. Treatment with ProSi113-TP in combination with paclitaxel in a paclitaxel-resistant ovarian carcinoma xenografted murine model, resulted in an impressive reduction of tumor volume greater than 95%. Our results revealed a promising activity of Si113 prodrugs and pave the way for their further development against resistant cancer.

Synthesis and antineoplastic activity of ethylene glycol phenyl aminoethyl ether derivatives as FOXM1 inhibitors

FOXM1 signalling pathways are highly expressed in multiple human cancers. Based on the crystal structure of the FOXM1 DNA binding domain, our preliminary research found ethylene glycol (4-benzyloxyphenyl) cyclopentylaminoethyl ether XST20, which could inhibit ovarian cancer cell proliferation and showed a medium affinity for the truncated protein FOXM1. This study intended to develop a FOXM1 inhibitor with stronger affinity and higher efficiency to be utilized as a molecular tool and drug candidate. We evaluated the optimization direction through molecular docking and systematically modified the structure of XST20. A novel class of ethylene glycol phenyl aminoethyl ether derivatives were synthesized, their anticancer activity and mechanism were evaluated, and the structure-activity relationship was summarized. Compound S2 showed a stronger affinity for FOXM1 and improved its activity with a broad-spectrum anticancer effect. S2 displayed selective antiproliferative activity against cancer cells with high expression levels of FOXM1 proteins. S2 should be a good chemobiological tool and a potential leading compound for future studies of anticancer drugs targeting FOXM1.

A theranostic probe of indoleamine 2,3-dioxygenase 1 (IDO1) for small molecule cancer immunotherapy

Discovering novel small molecules for cancer immunotherapy represents a promising but challenging strategy in future cancer treatment. Herein, we designed the first theranostic fluorescent probes to efficiently detect and inhibit the enzymatic activity of 2,3-dioxygenase 1 (IDO1). Probe 6b is a highly active IDO1 inhibitor (IC

Discovery of pyrimidine-bridged CA-4 CBSIs for the treatment of cervical cancer in combination with cisplatin with significantly reduced nephrotoxicity

A series of pyrimidine-bridged CA-4 derivatives (9a-u) targeting colchicine site were designed, synthesized and evaluated. Among them, the most potent compound 9j showed favorable anti-proliferative activities against a panel of cervical cancer cells (IC

Novel PROTACs targeting tissue transglutaminase (TG2) suppress tumorigenicity of ovarian cancer cells

Tissue transglutaminase (TG2), a multifunctional enzyme involved in protein crosslinking through transamidation, fibronectin-integrin interactions and GTP hydrolysis, is upregulated in cancer. Due to its diverse functions, TG2 has been a challenging therapeutic target. Here, we investigate the use of PROteolysis TArgeting Chimeras (PROTACs) to degrade TG2 and inhibit its tumor-promoting functions in ovarian cancer models. We describe a novel family of VHL based PROTACs using a ligand that binds to the TG2 fibronectin interacting domain and a thiol ether PEG linker. Three structurally related PROTACs-P374, P404, and P405-induced significant proteasome dependent TG2 degradation at 24 h (p < 0.05), with stable effects at 48 h. These compounds also potently inhibited cell adhesion and migration (p < 0.005), outside-in signaling, and blocked TG2 enzymatic activity (p < 0.001). An unbiased evaluation using reverse phase protein array of P374-treated cells revealed 136 differentially expressed proteins, including protein networks related to cell adhesion and involved in extracellular matrix (ECM) interactions. P374 and P405 reduced omental colonization in vivo and P374 inhibited intraperitoneal tumor dissemination and growth. Visium HD based spatial profiling of human ovarian tumors identified TG2 as a highly enriched protein at the tumors invasive edge and the interface with the ECM. Together, our findings put forward novel TG2-targeting PROTACs which effectively degrade TG2, impair its functions, and block in-vivo tumor dissemination. These results highlight the potential development of TG2 degraders towards therapeutic targeting in ovarian cancer.

An insight into recent developments in imidazole based heterocyclic compounds as anticancer agents: Synthesis, SARs, and mechanism of actions

Design and synthesis of novel triazole-metronidazole boswellic acid hybrids for ovarian cancer targeting

In this study, we report the design, synthesis, and biological evaluation of a new series of triterpenoid metronidazole-linked 1H-1,2,3-triazole conjugates (16-23) as potential targeted therapies. These compounds were screened across a panel of ovarian cancer cell lines. The cytotoxic profiles of all β-AKBA and β-ABA metronidazole-triazole hybrids were evaluated against normal endothelial cells (HUVEC), cisplatin-sensitive ovarian cancer cells (A2780-S), and cisplatin-resistant cells (A2780-CP). Several derivatives showed enhanced cytotoxicity relative to their parent triterpenoids, with compound 21 exhibiting the most favourable selectivity index (SI ≈ 1.61), demonstrating preferential toxicity toward malignant cells while sparing normal cells. The selective cytotoxicity is controlled by reaching an ideal balance of molecular weight, topological polar surface area, hydrogen-bonding characteristics, and nitrogen-rich substituents, according to structure-activity relationship (SAR) studies. Computational docking studies further confirmed that compound 21 displays strong complementarity and robust binding affinity toward PARP6, suggesting a possible mechanism of action through PARP6 modulation. The study provides a promising platform for advancing triterpenoid-based targeted therapeutics in ovarian cancer therapy.

A combination of salinomycin or its C20 triphenylphosphonium-conjugated derivative with carboplatin leads to autophagy in ovarian cancer cells – An in vitro study

Ovarian cancer (OvCa) remains a major therapeutic challenge due to limited treatment options and frequent late-stage diagnosis, which contribute to high recurrence rates and mortality. Advances in synthetic organic chemistry and the development of novel oncology-targeted molecules offer promising new directions. In this study, we aimed to evaluate salinomycin (SAL) and its semisynthetic derivatives as potential candidates for OvCa therapy. Among the synthesized C20 SAL derivatives, we selected compound 8, featuring a triphenylphosphonium (TPP

Synthesis and biological evaluation of novel fused pyridopyrimidine derivatives as topoisomerase I inhibitors and as potential antitumor agents: promising results in lung, ovary and gastric cancer

The topoisomerase I (TOP1) enzymatic inhibition was investigated using novel pyrimidine and quinazolinone derivatives. First, the synthesis of these compounds was performed by intramolecular cycloaddition reaction of functionalized aminoalcohols, aminoesters and aldimines, obtained by the condensation of 2-aminopyridine and unsaturated aldehydes, affording corresponding pyrido[1,2-a]pyrimidine derivatives, pyrido[2,1-b]quinazolin-11-one derivatives and hybrid chromeno[4,3-d]pyrido[1,2-a]pyrimidine compounds respectively with good to high general yields. The vast majority of prepared products showed notable and excellent activity as inhibitors of TOP1. The cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV-3), human gastric adenocarcinoma (AGS), human undifferentiated gastric adenocarcinoma derived from the metastatic lymph node (HGC27), and on non-cancerous lung fibroblasts cell line (MRC-5) was also screened. Dihydrochromeno[4,3-d]pyrido[1,2-a]pyrimidine 9b was the most cytotoxic compound with IC

Asiatic acid as a leading structure for derivatives combining sub-nanomolar cytotoxicity, high selectivity, and the ability to overcome drug resistance in human preclinical tumor models

Amides and rhodamine B conjugates of different pentacyclic triterpene acids have been shown outstanding cytotoxicity for human tumor cells. Starting from asiatic acid, a new rhodamine B hybrid has been synthesized, and its cytotoxic activity was investigated employing several human tumor cell lines (A375 (melanoma), HT29 (colorectal carcinoma), MCF7 (breast adenocarcinoma), A2780 (ovarian carcinoma), HeLa (cervical carcinoma), (NIH 3T3 (non-malignant murine fibroblasts). For these conjugates of this kind it has been established that the spacer attached to the carboxyl group at ring E governs the magnitude of the cytotoxicity. These asiatic acid - rhodamine B conjugates were highly cytotoxic for human tumor cell lines but also selective. For example, 7, an acetylated homopiperazinyl spacered rhodamine B conjugate, held an EC

Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC

Pharmacological advances and therapeutic applications of niclosamide in cancer and other diseases

Computer-aided identification, synthesis, and biological evaluation of DNA polymerase η inhibitors for the treatment of cancer

In cancer cells, Pol η allows DNA replication and cell proliferation even in the presence of chemotherapeutic drug-induced damages, like in the case of platinum-containing drugs. Inhibition of Pol η thus represents a promising strategy to overcome drug resistance and preserve the effectiveness of chemotherapeutic drugs. Here, we report the discovery of a novel class of Pol ƞ inhibitors, with 35 active close analogs. Compound 21 (ARN24964) stands out as the best inhibitor, with an IC

Synthesis, mechanisms of action, and toxicity of novel aminophosphonates derivatives conjugated irinotecan in vitro and in vivo as potent antitumor agents

Twenty novel aminophosphonates derivatives (5a-5j and 6a-6j) conjugated irinotecan were synthesized through esterification reaction, and evaluated their anticancer activities using MTT assay. In vitro evaluation revealed that they displayed similar or superior cytotoxicity compared to the positive drug irinotecan against A549, MCF-7, SK-OV-3, MG-63, U2OS and multidrug-resistant (MDR) SK-OV-3/CDDP cancer cell lines. Among them, 9b displayed the most potent activity, with IC

Therapeutic strategies to overcome cisplatin resistance in ovarian cancer

Ovarian cancer (OC) is one of the most common gynecologic tumors worldwide and one with the highest mortality. Cisplatin (DDP) is the first platinum-based complex approved by the Food and Drug Administration (FDA) to treat patients with OC. Despite a good initial response rate, most patients receiving DDP treatment will ultimately develop resistance via various complicated mechanisms, leading to therapeutic failure and increased mortality. Multiple resistance pathways have been identified as potentially key areas of intervention. In this review, chemotherapeutic drugs and phytochemicals developed to overcome cisplatin-resistance ovarian cancer (CROC) were discussed. Targeted inhibition or specific drugs are effective against the DDP-resistance phenotype by inhibiting resistance or increasing cytotoxic efficacy. Phytochemicals as chemosensitizers offer novel treatment strategies for CROC patients by reducing chemoresistance and increasing drug efficacy. Due to the complexity of the DDP-resistance mechanism, the treatment of OC needs to improve specificity and effectiveness, and multi-path cooperative therapy is undoubtedly one of the best options. We discuss extensively the role of combination therapy in reversing DDP-resistance in OC and the significance of using a nanoparticle delivery system in this context. Suggestions for potential therapeutic strategies for CROC treatment will help discover more effective and specific regimens to overcome DDP-resistance.

Discovery of 2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives that regulated HPV relevant cellular pathway and prevented cervical cancer from abnormal proliferation

Human papillomavirus (HPV) is a well-established etiological factor for cervical cancer, and the expression of oncogenic protein E7 is crucial for carcinogenesis. Herein, virtual screening was performed and 2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives were designed, synthesized as antineoplastic agents, and evaluated for their anti-tumor activities. Among them, the most promising compound H1 showed specific anti-proliferation ability against HeLa cells (IC

A peptide-salinomycin conjugate with a bystander effect reduces the stemness characteristics of ovarian cancer cells and enhances drug sensitivity

Salinomycin (Sal) has attracted considerable attention in the field of tumor treatment, especially for its inhibitory effect on cancer stem cells (CSCs) and drug-resistant tumor cells. However, its solubility and targeting specificity pose significant challenges to its pharmaceutical development. Sal-A6, a novel peptide-drug conjugate (PDC), was formed by linking the peptide A6 targeting the CSC marker CD44 with Sal using a specific linker. This conjugation markedly enhances the physicochemical properties of Sal and compared to Sal, Sal-A6 demonstrated a significantly increased activity against ovarian cancer. Furthermore, Sal-A6, employing a disulfide bond as a linker, exhibited bystander killing effect. Moreover, it induces substantial cytotoxic effect on both cancer stem cells and drug-resistant cells in addition to enhance chemosensitivity of resistant ovarian cancer cells. In summary, the results indicated that Sal-A6, a novel PDC derived from Sal, has potential therapeutic applications in the treatment of ovarian cancer and drug-resistant patients. Additionally, this discovery offers insights for developing PDC-type drugs using Sal as a foundation.