Biology subjects

Nurmemmedov, E.

Publications and source records attributed to Nurmemmedov, E..

8 recordsLinked to original sources

bioRxiv2026

Targeting the NuRD Component, CHD4, Impairs Foxp3+ Treg Cell Production and Function and Promotes Anti-Tumor Immunity

Little is known about why Foxp3 regulatory T (Treg) cells require at least three HDAC1/HDAC2-containing chromatin-remodeling complexes (NuRD, Sin3 and CoREST), or whether selective disruption of these complexes can be exploited to enhance antitumor immunity. Here, we investigated the role of chromodomain helicase DNA- binding protein 4 (CHD4), the ATP-dependent remodeling subunit of the NuRD complex, in Treg biology. Conditional deletion of Chd4 in Foxp3 Tregs resulted in severe systemic autoimmunity and early lethality, accompanied by reduced Foxp3 expression, impaired Treg suppressive function, and loss of Treg lineage stability. Transcriptomic analyses demonstrated that CHD4 deficiency closely phenocopied Hdac2 deletion, whereas quantitative proteomic analyses revealed that CHD4 assembles into highly conserved NuRD complexes in both Treg and conventional CD4 T cells. These findings indicate that the selective dependence of Tregs on CHD4 does not arise from the formation of lineage-specific protein complexes but rather from the unique epigenetic program maintained by CHD4-containing chromatin-remodeling complexes that is required for Treg differentiation and stability. Using a novel cellular target-engagement platform, we identified CH41, a potent small-molecule inhibitor of CHD4 that recapitulated the effects of genetic CHD4 ablation on Treg function. Pharmacological inhibition of CHD4 impaired intratumoral Treg accumulation and function and significantly inhibited the growth of lung and hepatocellular carcinomas in immunocompetent, but not immunodeficient, mice, without inducing systemic autoimmunity. Collectively, our findings identify CHD4 as a critical epigenetic regulator of Treg lineage stability and establish pharmacological targeting of the CHD4/NuRD axis as a promising strategy to selectively disrupt tumor-associated Tregs and enhance antitumor immunity.

cancer biology↗

bioRxiv2026

Abbapolin inhibitors of the PLK1 PBD as Prostate Cancer Therapeutics, in vivo activity and synergy with androgen therapy

Polo-like kinase 1 (PLK1) is an established therapeutic target in cancer; however, ATP-competitive kinase inhibitors have shown limited clinical success because of toxicity, acquired resistance, and incomplete inhibition of non-catalytic PLK1 functions. Targeting the Polo-box domain (PBD), which regulates PLK1 localization and substrate recognition, represents an alternative therapeutic strategy but has been hindered by the lack of selective, cell-active small molecules. Here, the optimization and biological characterization of abbapolins, a series of non-peptidic PLK1 PBD inhibitors developed using the REPLACE strategy are described. Structure-guided optimization and screening across the NCI-60 cancer cell panel identified compounds with preferential activity against prostate cancer cells. Proteomic analyses demonstrated that cellular sensitivity correlated with PLK1 protein abundance, supporting an on-target mechanism of action. Abbapolins directly engaged PLK1 in cells, induced selective degradation of endogenous PLK1, and suppressed long-term clonogenic growth. Lead compounds demonstrated favorable pharmacokinetic properties and significantly inhibited prostate tumor growth in xenograft models without detectable systemic toxicity. PLK1 abundance was significantly reduced in treated tumors and correlated with tumor response, identifying PLK1 degradation as a potential pharmacodynamic biomarker. Abbapolins also synergized with enzalutamide in castration- resistant prostate cancer cells, supporting their potential as combination therapies for advanced disease. Collectively, these studies establish selective inhibition of the PLK1 Polo-box domain as a viable therapeutic strategy, provide in vivo proof-of-concept for the REPLACE approach, and identify abbapolins as promising leads for advanced prostate cancer.

cancer biology↗

bioRxiv2026

ADT-030, a novel PDE10 inhibitor, demonstrates potent antitumor activity in pancreatic ductal adenocarcinoma

Phosphodiesterase 10 (PDE10) has been noted to be highly expressed in multiple types of cancer and is crucial for the growth and maintenance of cancer cells found in colon, lung, and ovarian cancers. Here, we studied a novel orally bioavailable PDE10 inhibitor, ADT-030, and found that it potently inhibits the proliferation and clonogenicity of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cells at levels that block recombinant PDE10. ADT-030 also inhibited PDAC cell motility and triggered G2/M cell cycle halt and programmed cell death. These impacts were facilitated by raised cAMP/cGMP levels, activation of PKA/PKG, reduced {beta}-catenin and RAS signaling. Notably, ADT-030 diminished the proliferation of PDAC cells with KRASG12D and KRASG12C mutations that were resistant to both allele-specific and pan-RAS inhibitors. When administered orally, ADT-030 markedly decreased tumor growth, lowered the metastasis to the lungs and liver, and enhanced survival rates without causing systemic toxicity in both syngeneic and patient-derived xenograft (PDX) models of PDAC. ADT-030 also increased chemotherapy response in orthotopic PDAC models. Immune phenotyping and single-cell RNA sequencing revealed remodeling of the tumor microenvironment by ADT-030 with a more favorable anti-tumor immune profile. The findings suggest that ADT-030 holds promise as a potential drug development candidate for treating KRAS-mutant PDAC by simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects.

cancer biology↗

bioRxiv2025

MICRO-TAG enzyme complementation enables quantification of cellular drug-target engagement in temperature series

Drug discovery for challenging drug targets necessitates the proteomic complexities of the cellular milieu for contextual target folding and function. Conventional biophysical methods for assessing drug interaction with a target are often not sufficiently suited for drug discovery as they impose acellular environment on the target and rely on recombinant purified protein material. In contrast, cell target engagement offers a powerful paradigm for drug discovery, through measurement of transitions in the thermodynamic state of a target protein, as it engages with drug molecules in the cell. Split-enzyme cell target engagement methods offer scaled utility during early drug discovery. Here, we describe a novel highly sensitive and scalable fluorescence-based cell target engagement method that leverages complementation of split-RNase S. This offers a unique combination of procedural and biophysical advantages, enabling its seamless integration with various instruments and applications designed for fluorescence detection. Most importantly, this new method allows for quantitation of cell target engagement in programmable temperature series format, consistent with conventional thermal shift assays, rather than at a single melting temperature. We demonstrate the sensitivity and versatility of this approach for drug discovery using targets MAPK1, KRAS, and UBE2N.

biochemistry↗

bioRxiv2024

Increased interaction between connexin43 and microtubules is critical for glioblastoma stem-like cell maintenance and tumorigenicity.

Glioblastoma (GBM) is the most common primary tumor of the central nervous system. One major challenge in GBM treatment is the resistance to chemotherapy and radiotherapy observed in subpopulations of cancer cells, including GBM stem-like cells (GSCs). These cells hold the ability to self-renew or differentiate following treatment, participating in tumor recurrence. The gap junction protein connexin43 (Cx43) has complex roles in oncogenesis and we have previously demonstrated an association between Cx43 and GBM chemotherapy resistance. Here, we report, for the first time, increased direct interaction between non-junctional Cx43 with microtubules in the cytoplasm of GSCs. We hypothesize that non-junctional Cx43/microtubule complexing is critical for GSC maintenance and survival and sought to specifically disrupt this interaction while maintaining other Cx43 functions, such as gap junction formation. Using a Cx43 mimetic peptide of the carboxyl terminal tubulin-binding domain of Cx43 (JM2), we successfully ablated Cx43 interaction with microtubules in GSCs. Importantly, administration of JM2 significantly decreased GSC survival in vitro, and limited GSC-derived tumor growth in vivo. Together, these results identify JM2 as a novel peptide drug to ablate GSCs in GBM treatment.

cancer biology↗

bioRxiv2018

Targeting Wnt Signaling To Overcome PARP Inhibitor Resistance

Epithelial ovarian cancer (EOC) has one of the highest deaths to incidence ratios. High grade serous ovarian carcinoma (HGSOC) is the most common and deadliest EOC histotype because of the lack of secondary therapeutic options following debulking surgery and platinum/taxane-based chemotherapies. For recurrent chemosensitive HGSOC, poly(ADP)-ribose polymerase inhibitors (PARPi; olaparib, rucaparib, or niraparib) represent an emerging treatment strategy. While PARPi are most effective in homologous recombination DNA repair-deficient (HRD) HGSOCs, more recent studies have observed a significant clinical benefit in non-HRD HGSOCs. However, all HGSOC patients are likely to acquire resistance to PARPi. Therefore, there is an urgent clinical need to better understand PARPi resistance, and to introduce novel combinatorial therapies to overcome PARPi resistance and extend HGSOC disease-free intervals. Utilizing a two BRCA2-mutated and one BRCA-wildtype HGSOC cell lines that are olaparib sensitive, we established resistant cells. Transcriptome analysis of the matched olaparib-sensitive versus resistant cells did not detect BRCA2 reversion mutations, but revealed activation of Wnt/TCF signaling pathway, as TCF transcriptional activity was significantly increased in PARPi-resistant cells. In parallel, forced activation of Wnt signaling in PARPi-sensitive cells via WNT3A stimulation reduced response to PARPi. In a recurrent-HGSOC PARPi insensitive patient-derived xenograft model there was an increase in a Wnt/TCF transcriptional target. PARPi resistant cells were sensitive to inhibition of Wnt signaling using the FDA-approved compound, pyrvinium pamoate, which has been shown to inhibit Wnt signaling. We observed that combining pyrvinium pamoate with olaparib resulted in a significant decrease in tumor burden and number of tumor nodules. This study demonstrates that Wnt signaling can mediate PARPi resistance in HGSOC and provides a clinical rationale for combining PARPi and Wnt inhibitors.

cancer biology↗

bioRxiv2018

Structure of WT1 zinc fingers bound to its cognate DNA: Implications of the KTS insert

WT1 is a transcription factor with a DNA binding N-terminal domain containing four C2H2-type zinc fingers. In order to perform its role as a transcription factor, WT1 needs to specifically recognize and properly bind to its target DNA. How this is done is still not completely clear. Two of WT1s major isoforms are distinguished by the presence or absence of a 3 amino acid insert, Lysine-Threonine-Serine (KTS) in the linker between zinc-fingers 3 and 4. This KTS insert is conserved throughout all life forms expressing WT1. The -KTS isoform, which acts as a transcription factor, binds DNA with higher affinity than the +KTS isoform, which is thought to participate in RNA splicing and interaction with partner proteins. This study was aims at elucidating the effect of the KTS insert on DNA binding. Here we present the crystal structure of WT1 zinc fingers 2-4, with and without the KTS insert, bound to the WT1 9-base pair cognate DNA sequence, refined to 1.9 [A] and 2.5 [A] respectively. The structures show that the +KTS isoform of WT1 recognizes DNA with the same specificity as the -KTS isoform. The only differences in the DNA bound conformation of the two isoforms are found within the linker containing the KTS, and these mainly involve the loss of the C-capping interactions thought to stabilize the complex. These structures provide the molecular detail necessary for the interpretation of the WT1 transcriptional DNA recognition and validation of its transcriptional targets.

biophysics↗

bioRxiv2018

Structural view on the role of WT1’s zinc finger 1 in DNA binding

The WT1 protein is a transcription factor that controls genes involved in cell proliferation, differentiation and apoptosis. It has become increasing apparent that WT1 can act both as a tumor suppressor and oncogene in a tissue specific manner. This opposing role of WT1 is linked to its underlying transcriptional regulatory function, which involves the specific binding to its regulatory elements on gene promoters. WT1 binds DNA using it C-terminal domain made up of 4 C2H2-typ zinc fingers. This same zinc finger domain is used to bind RNA and proteins and it is still not clear how each zinc finger contributes to this promiscuous binding behavior. The molecular details of DNA binding by zinc finger 2 to 4 have been described but it remains to be determined whether or not zinc finger 1 binds DNA and if so whether it exhibits any DNA binding specificity. We present the X-ray structures of zinc finger 1 to 3 bound to a 9 bp and an 8 bp DNA. The two structures refined to 1.7 [A], show no DNA binding specificity for zinc finger 1. The only DNA interactions involving zinc finger 1 are crystal-packing interactions with a symmetry related molecule. In the structure of zinc finger 1 to 3 bound to the 9 bp DNA we observe a shift in the DNA binding positions for zinc fingers 2 and 3. These structures provide molecular detail into the WT1-DNA interaction showing that zinc finger 1 only modestly contributes to DNA binding affinity through transient interactions. The dislocation of zinc finger 2 and 3 emphasizes the importance of zinc finger 4 for maintaining gene transcriptional specificity.

biophysics↗