cyclopamine / University of Macau - LARVOL DELTA

THE SMOOTHENED AGONIST (SAG) ENHANCES MITOCHONDRIAL MEMBRANE POTENTIAL AND EXERTS ANTIOXIDATIVE ACTIONS AGAINST ALZHEIMER'S DISEASE (ADPD 2026) - "This SAG-dependent effect was reversed by the smoothened antagonist cyclopamine. We conclude that SAG-mediated protective effects in AD models may involve the quality control of mitochondria and the mitigation of oxidative stress."

Alzheimer's Disease • CNS Disorders • CASP3 • SHH

Pharmacokinetic/pharmacodynamic correlation and biodistribution of paclitaxel and cyclopamine from M-CPA/PTX in HCC mice following multiple dosing (AACR 2026) - "The 3D PK/PD correlation was established for tumor growth inhibition (%), with tumor concentrations of PTX and CPA in individual mice. In conclusion, the biodistributions of PTX and CPA following multiple IV dosing in an HCC mouse model were characterized, and a 3D PK/PD correlation was established with PX and CPA uptakes in tumor, potentially enabling future efficacy projection.Table 1: Biodistribution of PTX and CPA from M-CPA/PTX"

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

Cyclopamine tartrate enhances antitumor immunity and suppresses triple-negative breast cancer growth (AACR 2026) - "These data indicate that CycT shows significant antitumor effects in a TNBC model while promoting CD8⁺ T-cell infiltration and activation. The results suggest that CycT reprograms the tumor microenvironment to become immune-accessible, providing a mechanistic basis for future combination strategies with immune checkpoint blockade in TNBC."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • PD-1

Hierarchical micro-/nanostructured hydroxyapatite scaffolds promote osteoporotic bone regeneration via activation of hedgehog and HIF-1α signaling. (PubMed, Bioact Mater) - "Pharmacological inhibition with cyclopamine, as well as siRNA-mediated knockdown of GLI1 or HIF-1α, significantly attenuated these pro-osteoangiogenic markers, confirming functional crosstalk between Hedgehog and hypoxia signaling pathways in response to scaffold-induced topographic cues. These findings establish nHA morphology as a critical topographical regulator of bone regeneration and provide a versatile platform for designing adaptive bioceramics tailored to osteoporotic bone repair."

Journal • Osteoporosis • GLI1 • HIF1A

SHH pathway inhibition and astrocyte co-culture induce distinct responses in glioblastoma and cancer stem cells. (PubMed, Sci Rep) - "By comparing treatment and culture context independently, cyclopamine-mediated SHH inhibition and astrocyte-dependent 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

Mediolateral neural patterning during gastrulation precedes dorsoventral patterning in chick and frog. (PubMed, Dev Biol) - "dorsoventral gene expression is preceded by topographically "homologous" mediolateral expression of some key components. The initial functional analysis of early hedgehog signaling in the chick points to as yet unknown mediolateral interactions during gastrulation which lead to prospective dorsoventral differentiation of the neural plate."

Journal • PAX3 • PAX7

Natural products as payloads for antibody-drug conjugates: Cyclopamine linked to cetuximab for hedgehog pathway inhibition. (PubMed, Bioorg Chem) - "The linker-payload system was stable in plasma yet released gradually cyclopamine at pH 5.5. These results suggest the feasibility of using natural products as payloads for the construction of ADCs to inhibit HH signalling in cancer cells."

Journal • Melanoma • Oncology • Solid Tumor • EGFR • GLI1 • GLI2

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