ACS Pharmacology and Translational Science最新文献

FTO, an N ⁶-methyladenosine (m⁶A) and N ⁶,2'-O-dimethyladenosine (m⁶A_m) RNA demethylase, is a promising target for treating acute myeloid leukemia (AML) due to the significant anticancer activity of its inhibitors in preclinical models. Here, we demonstrate that the FTO inhibitor FB23-2 suppresses proliferation across both AML and CML cell lines, irrespective of FTO dependency, indicating an alternative mechanism of action. Metabolomic analysis revealed that FB23-2 induces the accumulation of dihydroorotate (DHO), a key intermediate in pyrimidine nucleotide synthesis catalyzed by human dihydroorotate dehydrogenase (hDHODH). Notably, structural similarities between the catalytic pockets of FTO and hDHODH enabled FB23-2 to inhibit both enzymes. In contrast, the hDHODH-inactive FB23-2 analog, ZLD115, required FTO for its antiproliferative activity. Similarly, the FTO inhibitor CS2 (brequinar), known as one of the most potent hDHODH inhibitors, exhibited FTO-independent antileukemic effects. Uridine supplementation fully rescued leukemia cells from FB23-2 and CS2-induced growth inhibition, but not ZLD115, confirming the inhibition of pyrimidine synthesis as the primary mechanism of action underlying their antileukemic activity. These findings underscore the importance of considering off-target effects on hDHODH in the development of FTO inhibitors to optimize their therapeutic potential and minimize unintended consequences.

FTO, an N⁶-methyladenosine (m⁶A) and N⁶,2′-O-dimethyladenosine (m⁶A_m) RNA demethylase, is a promising target for treating acute myeloid leukemia (AML) due to the significant anticancer activity of its inhibitors in preclinical models. Here, we demonstrate that the FTO inhibitor FB23-2 suppresses proliferation across both AML and CML cell lines, irrespective of FTO dependency, indicating an alternative mechanism of action. Metabolomic analysis revealed that FB23-2 induces the accumulation of dihydroorotate (DHO), a key intermediate in pyrimidine nucleotide synthesis catalyzed by human dihydroorotate dehydrogenase (hDHODH). Notably, structural similarities between the catalytic pockets of FTO and hDHODH enabled FB23-2 to inhibit both enzymes. In contrast, the hDHODH-inactive FB23–2 analog, ZLD115, required FTO for its antiproliferative activity. Similarly, the FTO inhibitor CS2 (brequinar), known as one of the most potent hDHODH inhibitors, exhibited FTO-independent antileukemic effects. Uridine supplementation fully rescued leukemia cells from FB23-2 and CS2-induced growth inhibition, but not ZLD115, confirming the inhibition of pyrimidine synthesis as the primary mechanism of action underlying their antileukemic activity. These findings underscore the importance of considering off-target effects on hDHODH in the development of FTO inhibitors to optimize their therapeutic potential and minimize unintended consequences.

Hepatocellular carcinoma (HCC) represents the predominant form of primary liver cancer, yet early, precise, and noninvasive detection continues to pose a considerable clinical challenge. Glypican-3 (GPC3), a membrane-bound proteoglycan, is markedly overexpressed in most HCC cases, while exhibiting low expression in normal and hepatitis-affected liver tissues. Given its crucial role in malignant transformation and tumor progression, GPC3 emerges as a compelling target for imaging. In this study, we developed and evaluated 2 ⁶⁸Ga-labeled GPC3-targeted positron emission tomography (PET) probes, each incorporating either polyethylene glycol (PEG) or 4-(p-methylphenyl)butanoic acid (an albumin-binding moiety). Comparative analyses revealed that ⁶⁸Ga-ALB-GBP, which includes the albumin-binding moiety, exhibited superior in vivo stability, enhanced tumor uptake, and an improved tumor-to-liver ratio relative to ⁶⁸Ga-PEG₂-GBP in subcutaneous HCC mouse models. Micro-PET/computed tomography imaging of orthotopic liver cancer with ⁶⁸Ga-ALB-GBP demonstrated a tumor-to-liver ratio of 2.29 ± 0.13 and a tumor-to-muscle ratio of 13.03 ± 1.63 at 3 h postinjection, outperforming the performance of the clinically used ¹⁸F-fluorodeoxyglucose PET imaging. These findings suggest that ⁶⁸Ga-ALB-GBP is a promising diagnostic tool for HCC and a strong candidate for clinical translation with potential utility in both diagnostic and therapeutic settings. Moreover, the incorporation of an albumin-binding moiety into PET tracers significantly extends blood circulation time, thereby enhancing bioavailability and facilitating high-contrast PET imaging.

Hepatocellular carcinoma (HCC) represents the predominant form of primary liver cancer, yet early, precise, and noninvasive detection continues to pose a considerable clinical challenge. Glypican-3 (GPC3), a membrane-bound proteoglycan, is markedly overexpressed in most HCC cases, while exhibiting low expression in normal and hepatitis-affected liver tissues. Given its crucial role in malignant transformation and tumor progression, GPC3 emerges as a compelling target for imaging. In this study, we developed and evaluated 2 ⁶⁸Ga-labeled GPC3-targeted positron emission tomography (PET) probes, each incorporating either polyethylene glycol (PEG) or 4-(p-methylphenyl)butanoic acid (an albumin-binding moiety). Comparative analyses revealed that ⁶⁸Ga-ALB-GBP, which includes the albumin-binding moiety, exhibited superior in vivo stability, enhanced tumor uptake, and an improved tumor-to-liver ratio relative to ⁶⁸Ga-PEG₂-GBP in subcutaneous HCC mouse models. Micro-PET/computed tomography imaging of orthotopic liver cancer with ⁶⁸Ga-ALB-GBP demonstrated a tumor-to-liver ratio of 2.29 ± 0.13 and a tumor-to-muscle ratio of 13.03 ± 1.63 at 3 h postinjection, outperforming the performance of the clinically used ¹⁸F-fluorodeoxyglucose PET imaging. These findings suggest that ⁶⁸Ga-ALB-GBP is a promising diagnostic tool for HCC and a strong candidate for clinical translation with potential utility in both diagnostic and therapeutic settings. Moreover, the incorporation of an albumin-binding moiety into PET tracers significantly extends blood circulation time, thereby enhancing bioavailability and facilitating high-contrast PET imaging.

Lung cancer is among the most common instances of cancer subtypes and is associated with high mortality rates. Due to the availability of fewer therapies and delayed clinical investigations, the number of cancer incidences is rising dramatically. This is possibly an effect of immune modulations and chemotherapeutic drugs that raises cancer resistance. Among the list, IL-6 and IL-17 are host-derived paradoxical effectors that attune immune responses in malignant lung cells. Their excessive release in the cytokine milieu stabilizes immunosuppressive phenotypes, resulting in cellular perturbations. During tumor development, the significance of these molecules is reflected in their potential to regulate oncogenesis by initiating a myriad of signaling events that influence tumor growth and the metastatic ability of benign cancer cells. Moreover, their transactivation contributes to antiapoptotic mechanisms and favors cancer cell survival via constitutive expression of immunoregulatory molecules. Co-evolution and gene duplication events could be the major drivers behind cytokine evolution, which have prompted generic changes and, hence, the additive effect. The evolutionary model and statistical analysis provide evidence about the cytokines ancestral relationships and site-specific conservation, which is more convincing as both cytokines share cysteine-knot-like structures important in maintaining structural integrity. Funneling through the findings could help find residues that serve a catalytic role in immune functioning. Designing peptides or subunit vaccine formulations against those conserved residues could aid in combating lung cancer pathogenesis.

Lung cancer is among the most common instances of cancer subtypes and is associated with high mortality rates. Due to the availability of fewer therapies and delayed clinical investigations, the number of cancer incidences is rising dramatically. This is possibly an effect of immune modulations and chemotherapeutic drugs that raises cancer resistance. Among the list, IL-6 and IL-17 are host-derived paradoxical effectors that attune immune responses in malignant lung cells. Their excessive release in the cytokine milieu stabilizes immunosuppressive phenotypes, resulting in cellular perturbations. During tumor development, the significance of these molecules is reflected in their potential to regulate oncogenesis by initiating a myriad of signaling events that influence tumor growth and the metastatic ability of benign cancer cells. Moreover, their transactivation contributes to antiapoptotic mechanisms and favors cancer cell survival via constitutive expression of immunoregulatory molecules. Co-evolution and gene duplication events could be the major drivers behind cytokine evolution, which have prompted generic changes and, hence, the additive effect. The evolutionary model and statistical analysis provide evidence about the cytokines ancestral relationships and site-specific conservation, which is more convincing as both cytokines share cysteine-knot-like structures important in maintaining structural integrity. Funneling through the findings could help find residues that serve a catalytic role in immune functioning. Designing peptides or subunit vaccine formulations against those conserved residues could aid in combating lung cancer pathogenesis.

Kirsten rat sarcoma (KRAS) is a frequently mutated oncogene responsible for several oncogenic KRAS variants and for driving tumor proliferation. Some nonsmall cell lung cancer (NSCLC) tumors exhibit KRAS G12C mutations, which can be targeted for inhibition using covalent and more recently noncovalent inhibitors. Sotorasib was the first FDA-approved G12C inhibitor that has shown efficacy in lung cancer patients, but with mixed responses. The lack of efficacy can be attributed to tumor heterogeneity (lack of G12C mutations) and/or inefficient delivery. Targeted KRAS G12C imaging has potential to identify NSCLC lesions with the targeted mutation and elucidate the oncogene’s role in driving tumor growth and correlating responses to treatment. Toward this goal, we have developed a sotorasib-based molecular agent for PET imaging and tested its efficacy in targeting tumor lesions with KRAS G12C mutations. Here, we describe the synthesis, in vitro and in vivo evaluation of an [¹²⁴I]I-Sotorasib analog in targeting G12C mutant tumor lesions using PET imaging.

Hematological cancers, such as lymphomas and leukemias, pose significant challenges in oncology, necessitating a deeper understanding of their molecular landscape to enhance therapeutic strategies. This article critically examines and discusses recent research on the roles of G protein-coupled receptors (GPCRs) in myeloma, lymphomas, and leukemias with a particular focus on pediatric acute lymphoblastic (lymphocytic) leukemia (ALL). By utilizing RNA sequencing (RNA-seq), we analyzed GPCR expression patterns in pediatric ALL samples (aged 3–12 years old), with a further focus on Class A orphan GPCRs. Our analysis revealed distinct GPCR expression profiles in pediatric ALL, identifying several candidates with aberrant upregulated expression compared with healthy counterparts. Among these GPCRs, GPR85, GPR65, and GPR183 have varying numbers of studies in the field of hematological cancers and pediatric ALL. Furthermore, we explored missense mutations of pediatric ALL in relation to the RNA gene expression findings, providing insights into the genetic underpinnings of this disease. By integrating both RNA-seq and missense mutation data, this article aims to provide an insightful and broader perspective on the potential correlations between specific GPCR and their roles in pediatric ALL.

Kirsten rat sarcoma (KRAS) is a frequently mutated oncogene responsible for several oncogenic KRAS variants and for driving tumor proliferation. Some nonsmall cell lung cancer (NSCLC) tumors exhibit KRAS G12C mutations, which can be targeted for inhibition using covalent and more recently noncovalent inhibitors. Sotorasib was the first FDA-approved G12C inhibitor that has shown efficacy in lung cancer patients, but with mixed responses. The lack of efficacy can be attributed to tumor heterogeneity (lack of G12C mutations) and/or inefficient delivery. Targeted KRAS G12C imaging has potential to identify NSCLC lesions with the targeted mutation and elucidate the oncogene's role in driving tumor growth and correlating responses to treatment. Toward this goal, we have developed a sotorasib-based molecular agent for PET imaging and tested its efficacy in targeting tumor lesions with KRAS G12C mutations. Here, we describe the synthesis, in vitro and in vivo evaluation of an [¹²⁴I]I-Sotorasib analog in targeting G12C mutant tumor lesions using PET imaging.