cyclopamine / University of Macau - LARVOL DELTA

Discovery of natural PDE-5 inhibitors in NO signalling pathways for the human erectile dysfunction management: a multi-layered in silico assessment. (PubMed, In Silico Pharmacol) - "The phytochemicals Daidzin, Maackiain, Rutecarpin, and Cyclopamine exhibited strong binding affinity with PDE-5, supported by stable MD simulations and favourable MM/PBSA energies. All compounds have shown comparably equal results with Sildenafil. The online version contains supplementary material available at 10.1007/s40203-025-00491-6."

Journal • Erectile Dysfunction

Apolipoprotein C1 functions as a target of thyroid carcinoma and synergistic effects with promising candidate-cyclopamine. (PubMed, Transl Oncol) - "Together, these results implicate APOC1 as a driver of PTC progression and immune evasion and identify cyclopamine as a promising therapeutic that acts, at least in part, through APOC1-related signaling. Our study thus provides a rationale for targeting APOC1 as a novel treatment strategy for papillary thyroid carcinoma."

Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • APOC1

Involvement of the hedgehog signaling pathway in liver diseases. (PubMed, Ann Hepatol) - "Treatment with cyclopamine, a natural alkaloid responsible for the inhibition of this pathway, has been used at an experimental level, resulting in the reversal of damage, which has contributed to the search for new complementary or specific therapeutic alternatives against these medically important diseases. This review summarizes the current knowledge concerning the role of Hh signaling in liver homeostasis and disease progression. A deeper understanding of this pathway may provide novel insights for the development of targeted interventions for liver disease."

Journal • Review • Hepatology • Liver Failure • Oncology

Advances in the microbial biosynthesis of therapeutic terpenoids. (PubMed, Curr Opin Biotechnol) - "Herein, this review describes foundational advances in synthetic biology and metabolic engineering as exemplified by efforts to biosynthesize prominent terpenoids (i.e. artemisinin, taxol, vinblastine, QS-21, and cyclopamine) in engineered microorganisms (e.g. Escherichia coli and Saccharomyces cerevisiae). Emerging methods that accelerate microbial biosynthesis campaigns (i.e. automation, machine learning, artificial intelligence, and combinatorial screening) are then discussed."

Journal • Review

A cell-based Sonic hedgehog signaling transduction system to identify additive and synergistic chemical interactions. (PubMed, Toxicol Sci) - "Compounds reported to target SHH ligand processing (RU-SKI 43, AY 9944, U18666A), SMO-mediated signal transduction (cyclopamine, vismodegib, piperonyl butoxide, cannabidiol), and GLI transcription factors (GANT 61, arsenic trioxide) reduced Shh pathway-driven reporter activity with AC50 values in the low micromolar range or below. In zebrafish embryos, combined exposure to piperonyl butoxide and cyclopamine also produced a synergistic increase in craniofacial dysmorphogenesis. These findings demonstrate the importance of tractable models that recapitulate complex signal transduction pathways to empirically test for additive and synergistic chemical interactions in risk assessment."

Journal

Dual mechanism nanomedicine targeting drug resistance in pancreatic ductal adenocarcinoma (PDAC) Free (AACRPanCa 2025) - "We comprehensively evaluated the antitumor activity of polymeric micelles encapsulating cyclopamine and paclitaxel (ONP-001). ONP-001 preferentially delivers CPA and PTX to tumors, modulates the tumor stroma to increase blood flow, and decrease fibrosis and hypoxia, and kills cancer cells, creating a tumor microenvironment that is less supportive of cancer growth. ONP-001 significantly extended survival compared to gemcitabine + nab-paclitaxel in a resistant disease model of PDAC, suggesting potential for clinical translation. Ongoing studies are exploring synergy with immunotherapy and optimal dosing strategies to support IND-enabling development."

Fibrosis • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

SAG1.3-derived Frizzled-targeting small molecule compounds. (PubMed, J Biol Chem) - "Screening of SAG1.3 derivatives identified compound 11 that competed with BODIPY-cyclopamine binding at different FZDs and inhibited WNT-induced FZD dynamics and β-catenin signaling in HEK293 cells. Furthermore, compound 11 blocked WNT-3A-induced Lgr5 gene expression in human primary hepatocyte spheroids and reduced the viability of RNF43-mutated but not RNF43-wildtype pancreatic cancer cells. Based on our data, we suggest that compound 11 acts on FZDs to limit WNT- and WNT-surrogate-induced receptor dynamics providing a valid proof-of-concept for targeting FZDs with small molecule compounds."

Journal • Fibrosis • Immunology • Oncology • Pancreatic Cancer • Solid Tumor • FZD6 • LGR5 • RNF43

The ciliary kinesin KIF7 controls the development of the cerebral cortex by acting differentially on SHH signaling in dorsal and ventral forebrain. (PubMed, Elife) - "These structural defects alter the cortical distribution of cIN, which moreover exhibit intrinsic migration defects and cortical trajectories resembling those of cyclopamine-treated cIN. Our results show that Kif7 deletion impairs the cortex development in multiple ways, exhibiting opposite effects on SHH pathway activity in the developing principal neurons and inhibitory interneurons."

Journal • CNS Disorders • GLI3 • SHH

Sonic Hedgehog signaling in spinal cord injury: mechanisms and therapeutic implications. (PubMed, Front Mol Neurosci) - "Various pharmacological agents including agonists (SAG, Purmorphamine and Shh-N) and antagonists (Cyclopamine, Vismodegib and Sonidegib) have been studied for their ability to modulate this pathway and enhance recovery in preclinical models. However, despite promising experimental outcomes, the clinical translation of these findings faces significant challenges, including delivery limitations, potential tumorigenicity, immune variability and the lack of robust human data. This review critically examines the molecular mechanisms and therapeutic potential of Shh signaling in SCI, highlights current limitations and conflicting evidence and outlines future directions to bridge the gap between preclinical findings and clinical application."

Journal • Review • CNS Disorders • Oncology • Orthopedics

A novel prognostic signature integrating disulfidptosis- and ferroptosis-related genes in acute myeloid leukemia. (PubMed, Clin Exp Med) - "Patients categorized as high-risk demonstrate enhanced benefits from cyclopamine, 443654, and 770041, whereas those classified as low-risk exhibit more pronounced advantages from cytarabine and AZD6244. The risk signature demonstrates superior prognostic accuracy compared to established signatures and mutated genes. In summary, our study may provide potential prognostic biomarkers and individualized precision therapy for AML patients."

Biomarker • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Inhibition of PI3K and Hedgehog Signaling Pathway Inhibits Hypoxia-Induced Vasculogenic Mimicry Formation in Ovarian Cancer Stem Cells. (PubMed, Balkan Med J) - "Moreover, both LY294002 and cyclopamine significantly reduced cell proliferation, invasion, and VM formation in vitro and in xenografted OCSCs. HIF-1α knockdown inhibits activation of the PI3K and Hedgehog signaling pathways, thereby reducing EET and VM formation in hypoxia-induced OCSCs."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CDH2 • CDH5 • HIF1A

SHH Pathway Inhibition and Astrocyte Co-culture Induce Distinct Responses in Glioblastoma and Cancer Stem Cells. (PubMed, Res Sq) - "By comparing treatment and culture context independently, cyclopamine-mediated SHH inhibition and astrocyte-depending signals use distinct but interacting effects on cell behavior...Astrocyte co-culture significantly modulates the molecular and phenotypic response of GBM cells to SHH inhibition, reshaping apoptotic and proliferative behaviors in both CSCs and bulk populations. These findings highlight the critical importance of the tumor microenvironment in therapeutic response and suggest that effective targeting of SHH signaling may require models that account for astroglial interactions."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CASP8 • CD133 • GLI1 • GLI3 • SUFU

Transcriptomic insights into Smoothened-dependent modulation of olfactory receptor genes in Apis mellifera ligustica: Implications for olfactory signal processing. (PubMed, Bull Entomol Res) - "Transcriptomic sequencing was performed on Apis mellifera ligustica antennae using Illumina HiSeq platform following administration of cyclopamine (inhibitor) and purmorphamine (agonist)...The changes in gene expression levels suggest that the activation or inhibition of AmelSmo may regulate the expression of olfactory receptors via the Hedgehog signalling pathway. It is speculated that AmelSmo may play a regulatory role in the olfactory system of bees."

Journal

Revealing key antioxidant compounds and mechanisms in Fritillaria Bulbus by metabolomics and network pharmacology. (PubMed, NPJ Sci Food) - "Molecular docking assessed that seven alkaloids (peimisine、imperialine、peimine、solasodine、veratramine、cyclopamine and jervine) exhibited good affinity for the antioxidant targets. Key therapeutic targets AKT1 and ESR1 mediate antioxidant mechanisms through PI3K/AKT signaling. These findings provide insights into interspecies differences in FB's antioxidant properties."

Journal • ER

Identification of genes involved in verazine biosynthesis in Veratrum grandiflorum and their heterologous production in Saccharomyces cerevisiae. (PubMed, BMC Plant Biol) - "Furthermore, the GAME4 gene with aldeylation of C-26 was also introduced, and the flask fermentation titer was increased to 175 ± 1.38 µg/L, which was the highest titer reported so far. These results provide a reference for high efficient heterologous biosynthesis study of verazine, and lay a foundation for the deciphering of cyclopamine biosynthetic pathway."

Journal

Regulation of Steroidal Alkaloid Biosynthesis in Bulbs of Fritillaria thunbergii Miq. By Shading and Potassium Application: Integrating Transcriptomics and Metabolomics Analyses. (PubMed, Biology (Basel)) - "Metabolome analysis showed that compared with those in the controls, peiminine, peimine, imperialine, solasodine, and cyclopamine were the most abundant steroidal alkaloids under K2S treatment...The interaction between FtFPS and FtAP2/ERF was verified through yeast two-hybrid experiments. These findings offer new insights into the steroidal alkaloid biosynthesis mechanism triggered in F. thunbergii by potassium application and shading, supporting ecological strategies to enhance steroidal alkaloid levels in this species."

Journal

Plumbagin, a natural derivative of 1,4-naphthoquinone, induces cyclopic phenomenon via increased apoptosis and ROS generation in the early stage of zebrafish embryos. (PubMed, Ecotoxicol Environ Saf) - "The cyclopia induced by PL was more severe than that of the positive controls, ethanol, forskolin, and cyclopamine...Thus, plants should be monitored for the presence of PL, given its strong cyclopia-inducing effects on animals. Due to the high frequency and severity of symptomatic zebrafish embryos in this study, PL's association with holoprosencephaly, specifically cyclopia, is undeniable."

Journal • CNS Disorders • Genetic Disorders

Hedgehog inhibitors exert anti-proliferation effects and synergistically interact with trastuzumab in HER2-positive gastric cancer models. (PubMed, Acta Oncol) - "This study highlights the potential of combining Hh inhibitors with trastuzumab as a therapeutic strategy for HER2-positive GC by targeting the AKT/mTOR pathway."

Journal • Preclinical • Gastric Cancer • Oncology • Solid Tumor • HER-2 • SMO

Combination Therapy for Overcoming Multidrug Resistance in Breast Cancer Through Hedgehog Signaling Pathway Regulation. (PubMed, Pharmaceutics) - " In this study, we combine cyclopamine (CYP, a potent Shh antagonist) with paclitaxel (PTX, an antitumor drug that can produce MDR) in a nano-drug delivery system (CYP NP and PTX NP) for the treatment of drug-resistant breast cancer. The combination of CYP NP and PTX NP augmented the antitumor effects in MCF-7/Adr-bearing nude mice models. The CYP NP and PTX NP combination offers a new therapeutic strategy in cancer treatment."

Journal • Breast Cancer • Oncology • Solid Tumor

Cyclopamine Attenuates Pulmonary Arterial Hypertension Development: Implications of Hedgehog Signaling Involvement for the Pathophysiology. (PubMed, FASEB J) - "RNA sequencing analysis of hypoxia-exposed hPASMCs revealed that the pathways related to extracellular matrix regulation were particularly recovered. Our animal model-based data revealed that HH signaling inhibition would improve PAH development by suppressing pulmonary vascular remodeling."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Combination therapies and novel delivery systems: a new frontier in overcoming TRAIL resistance in gastric cancer. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Combination therapies, integrating TRAIL with conventional chemotherapeutics like paclitaxel, cisplatin, and 5-fluorouracil, have shown promise in overcoming resistance by modulating apoptotic pathways and downregulating multidrug resistance genes. Additionally, novel agents like cyclopamine, decitabine, and genistein have emerged as effective TRAIL sensitizers by modulating apoptotic pathways and enhancing DR5 expression...This review emphasizes the need for a comprehensive understanding of the molecular underpinnings of TRAIL resistance and the potential of combination therapies and TRAIL delivery by nanoparticles and oncolytic viruses to enhance treatment outcomes in GC. Future research should focus on elucidating predictive biomarkers and optimizing therapeutic regimens to improve the clinical efficacy of TRAIL-based strategies in GC."

IO biomarker • Journal • Review • Gastric Cancer • Oncology • Solid Tumor • TNFRSF10B

Hedgehog signalling in solitary motile cilia: detection and role of Hedgehog factors in sperm functions and in vitro fertilization. (PubMed, Reproduction) - "Following sperm incubation under capacitating conditions with either Hh agonist (Smoothened agonist; SAG) or inhibitor (Cyclopamine), functional sperm parameters were measured, including motility, acrosome integrity, cell viability, intracellular calcium levels, cAMP concentrations, and in vitro fertilization outcome. Our study demonstrates that Hh signalling pathway regulates sperm motility and acrosome reaction, contributing to fertilization success. This report proposes new comprehensive signalling mechanisms that control male reproductive functions."

Journal • Preclinical • Gynecology • GLI3 • PTCH1

Pharmacokinetics of paclitaxel and cyclopamine co-administered via polymeric micelle in HCC mice (AACR 2025) - "The current non-surgical, first-line treatment, Sorafenib, is non-curative and does not improve patient quality of life. In conclusion, the PK of PTX and CPA in HCC mouse model from single and multiple dosing of M-CPA/PTX were characterized. Multiple dosing yielded no changes in CL and Vd of PTX, but increased CL and decreased AUC in CPA."

PK/PD data • Preclinical • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • MYC

Development and comprehensive preclinical evaluation of dual-drug polymeric micelles ONP-001 for PDAC and HCC (AACR 2025) - "This study comprehensively evaluated the mechanisms of polymeric micelles co-encapsulating cyclopamine (CPA) and paclitaxel (PTX) (M-CPA/PTX, ONP-001) and the effectiveness against HCC and PDAC...Studies in the transgenic HCC model also confirmed significantly greater antitumor efficacy for ONP-001, with no observed hepatotoxicity, compared to sorafenib treatment. ONP-001 was an effective therapeutic strategy for PDAC and HCC, targeting CSCs, modulating the stroma, and enhancing immunotherapy, at 5.0 mg/kg, TIW, with enhanced benefits when in combination regimens. ONP-001 was an effective therapeutic strategy for PDAC and HCC, targeting CSCs, modulating the stroma, and enhancing immunotherapy, at 5.0 mg/kg, TIW, with enhanced benefits when in combination regimens. Ongoing studies will further characterize the pharmacokinetics, tumor uptake and biodistribution of both drugs. The data supports further development of ONP-001 for potential future clinical development."

IO biomarker • Preclinical • Hepatocellular Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • IL15 • IL33 • KRAS

Plant Alkaloids as Promising Anticancer Compounds with Blood-Brain Barrier Penetration in the Treatment of Glioblastoma: In Vitro and In Vivo Models. (PubMed, Molecules) - "The toxic and adverse effect analysis suggests that alkaloids such as noscapine, lycorine, capsaicin, chelerythrine, caffeine, boldine, and colchicine show favorable therapeutic potential. However, tetrandrine, nitidine, harmine, harmaline, cyclopamine, cocaine, and brucine may pose greater risks than benefits...Overall, while plant alkaloids show promise in glioblastoma therapy, progress in assessing their BBB penetration remains limited. More comprehensive studies integrating glioma research and advanced drug delivery technologies are needed."

Journal • Preclinical • Review • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • BCL2