7-Hydroxystaurosporine (UCN-01) / National Cancer Institute - LARVOL DELTA

Unresolved Issues in Familial Mediterranean Fever: Is p.R202Q MEFV Variant Potentially Pathogenetic in Unleashing Inflammation? (PubMed, J Clin Immunol) - "Primary monocytes were incubated for 3 h in the presence of LPS or LPS + PKN1/2 inhibitor (UCN-01). Colchicine pretreatment was applied to assess its anti-inflammatory effect...The p.R202Q variant did not appear to affect pyrin function, albeit these patients presented cytological alterations similar to those observed in FMF patients. These changes may contribute to FMF pathophysiology by influencing inflammation progression."

Journal • Genetic Disorders • Inflammation • IL18 • IL1B

Assessing MEFV variant pathogenicity by ASC- Specks Flow Detection (CIS 2024) - "This filamentous structure creates multiplecaspase-1 activation sites and serves as a signal amplification mechanismfor inflammasome-mediated cytokine production.We designed a flow cytometry-based assay to assess ASC speck formationin peripheral circulating monocytes of FMF patients, serving as a readout toidentify cells undergoing inflammasome activation in response to variousstimuli, mainly Lipopolysaccharides, NLRP3 agonist (nigericin) or pyrinactivators (i.e., Clostridium Difficile Toxin A (TcdA), or the syntheticderivative of staurosporine UCN-01.Through analysis of 25 FMF patients, we showed that our ASC-Speck FlowAssay correctly identified FMF patients with pathogenic variants in MEFVcompared to healthy controls and patients with other autoinflammatorydisorders. Interestingly, our assay could also pinpoint patients withmonoallelic variants who display abnormal pyroptosome activation andcould benefit from appropriate therapy.Our study shows that accurate assessment..."

Amyloidosis • Genetic Disorders • Inflammation • NLRP3

Selective inhibition of DNA ligase IV provides additional efficacy to the treatment of anaplastic thyroid cancer. (PubMed, Front Oncol) - "The effect of caffeine (inhibitor of ATM and ATR) and UCN-01 (CHK1 inhibitor) was evaluated in cell cycle progression of thyroid cancer cells after γ-radiation or doxorubicin treatment. The combination of SCR7 with doxorubicin, significantly increased apoptosis and impaired ATC tumor growth in a xenograft mouse model compared to doxorubicin monotherapy. This study shows the therapeutic value of the combination of a DNA ligase IV inhibitor and DNA-damaging agents (doxorubicin and/or γ-radiation) for the treatment of anaplastic thyroid cancer."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • TP53BP1

Pyrin Inflammasome Activation Defines Colchicine-Responsive SURF Patients from FMF and Other Recurrent Fevers. (PubMed, J Clin Immunol) - "Syndrome of undifferentiated recurrent fever (SURF) is characterized by recurrent fevers, a lack of confirmed molecular diagnosis, and a complete or partial response to colchicine. In contrast to FMF, SURF patients, similar to PFAPA patients and healthy donors, did not exhibit pyrin inflammasome activation in response to UCN-01-mediated pyrin dephosphorylation. These data demonstrate that in vitro functional analysis of pyrin inflammasome activation can differentiate SURF from FMF and PFAPA patients, suggesting the involvement of the pyrin inflammasome in the pathophysiology of SURF."

Journal • Genetic Disorders • Inflammation • IL1B

Myt1 overexpression mediates resistance to cell cycle and DNA damage checkpoint kinase inhibitors. (PubMed, Front Cell Dev Biol) - "Promising drugs inhibiting kinases like Wee1 (Adavosertib), Wee1+Myt1 (PD166285), ATR (AZD6738) and Chk1 (UCN-01) have been developed, but clinical data has shown variable efficacy for them with poorly understood mechanisms of resistance. Elevated Myt1 levels also conferred resistance to inhibitors of ATR or Chk1 inhibitor. Our data supports that Myt1 overexpression is a common mechanism by which cancer cells can acquire resistance to a variety of drugs entering the clinic that aim to induce mitotic catastrophe by abrogating the G2/M checkpoint."

Journal • Oncology • CDK1 • PKMYT1

The p38/MK2 Pathway Functions as Chk1-Backup Downstream of ATM/ATR in G-Checkpoint Activation in Cells Exposed to Ionizing Radiation. (PubMed, Cells) - "However, although inhibition of ATR nearly completely abrogated the checkpoint, inhibition of Chk1 using UCN-01 generated only partial responses...These observations further expand the spectrum of p38/MK2 signaling to G-checkpoint activation, extend similar studies in cells exposed to other DNA damaging agents and consolidate a role of p38/MK2 as a backup kinase module, adding to similar backup functions exerted in p53 deficient cells. The results extend the spectrum of actionable strategies and targets in current efforts to enhance the radiosensitivity in tumor cells."

Journal • Oncology • CHEK1

Therapeutic targets in cancer treatment: Cell cycle proteins. (PubMed, Adv Protein Chem Struct Biol) - "This chapter explains the detail of cell cycle and checkpoint regulators, that are crucial to the malignant cellular process. The known CDKs inhibitors and their mechanism of action in various cancers have also been addressed as a step toward the development of a possibly novel technique for the design of new drugs against cell cycle kinase proteins."

Journal • Oncology • Solid Tumor

Evaluation of a Pooling Chemoproteomics Strategy with an FDA-Approved Drug Library. (PubMed, Biochemistry) - "Interestingly, numerous proteins were found to change upon drug treatment, including AMD1, ODC1, PRKX, PRKY, EXO1, AEN, and LRRC58 with 7-hydroxystaurosporine; C6orf64, HMGCR, and RRM2 with Sorafenib; SYS1 and ALAS1 with Venetoclax; and ATF3, CLK1, and CLK4 with Palbocilib. Thus, pooling chemoproteomics screening provides an efficient method for dissecting the molecular targets of compound libraries."

FDA event • Journal • Targeted Protein Degradation • ALK • ATF3 • RRM2 • TRAF3IP2

Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells. (PubMed, Sci Rep) - "As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results, we propose that the application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of the target specificity of multi-kinase inhibitors."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • PDK4

Comprehensive Bioinformatics Analysis of Toll-Like Receptors (TLRs) in Pan-Cancer. (PubMed, Biomed Res Int) - "The expression of TLR9 was significantly positively correlated with the drug sensitivity of fluphenazine, alectinib, carmustine, and 7-hydroxystaurosporine. TLR7 was significantly positively correlated with the drug sensitivity of alectinib. Our study reveals the significant role of TLRs family in pan-cancer and provides potential therapeutic strategies of cancer."

IO biomarker • Journal • Pan tumor • Acute Myelogenous Leukemia • Adrenal Cortex Carcinoma • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Clear Cell Renal Cell Carcinoma • Endocrine Cancer • Eye Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Germ Cell Tumors • Glioma • Hematological Malignancies • Leukemia • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • Testicular Cancer • Thymoma • Thymus Cancer • Thyroid Gland Carcinoma • Uveal Melanoma • TLR2 • TLR7 • TLR9

The impairment of DDR reduces XBP1s, further increasing DNA damage, and triggers autophagy via PERK/eIF2alpha in MM and IRE1alpha/JNK1/2 in PEL cells. (PubMed, Biochem Biophys Res Commun) - "Indeed, PARP and CHK1 inhibition by AZD2461 and UCN-01, by downregulating c-Myc, reduced the expression of XBP1s, constitutively expressed in these cells, and upregulated CHOP. Interestingly, given the role of XBP1s in regulating DDR, BRCA-1 expression level was reduced, exacerbating DNA damage. Finally, DDR/UPR interplay activated a pro-survival autophagy via PERK/eIF2alpha axis in MM and IRE1alpha/JNK axis in PEL cells, since in the latter case PERK/eIF2alpha activation could be prevented by KSHV that, as other herpesviruses, tries to avoid the blocks of protein translation that this pathway may induce."

Journal • Oncology • BRCA • BRCA1 • MAPK8 • MYC • UCN

p53 oligomerization status as an indicator of sensitivity of p53-wildtype neuroblastomas to the combination of DNA damaging agent and Chk1 inhibitor. (PubMed, PLoS One) - "In the current study, we investigated the response to the combination of a DNA damaging agent (SN38) and a Chk1 inhibitor (UCN-01) of four p53-wildtype neuroblastoma cell lines: SK-N-SH, SH-SY5Y, SK-N-AS, and Lan-5...Our study also showed no cytoplasmic accumulation of p53 in these cells contrary to some previous reports. The results of this study suggest that oligomerization status may serve as an indicator of sensitivity of p53-wildtype tumors to the therapeutic combination of DNA damaging agent and Chk1 inhibitor."

Journal • Neuroblastoma • Oncology • Solid Tumor • CDKN1A

Computationally prioritized drugs inhibit SARS-CoV-2 infection and syncytia formation. (PubMed, Brief Bioinform) - "Two compounds, 7-hydroxystaurosporine and bafetinib, show synergistic antiviral effects in vitro and strongly inhibit viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information for de novo drug design, the relevant chemical substructures of the identified drugs are extracted to provide a chemical vocabulary that may help to design new effective drugs."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

The structural basis for high affinity binding of α1-acid glycoprotein to the potent anti-tumour compound UCN-01. (PubMed, J Biol Chem) - "Solution NMR suggests AGP2 undergoes a significant conformational change upon ligand binding, but also that it uses a common set of sidechains with which it captures key groups of UCN-01 and other small molecule ligands. We anticipate that this structure and supporting NMR data will facilitate rational re-design of small molecules that could evade AGP and therefore improve tissue distribution."

Journal • Immune Modulation • Inflammation • Oncology

DNA damage triggers an interplay between wtp53 and c-Myc affecting lymphoma cell proliferation and KSHV replication. (PubMed, Biochim Biophys Acta Mol Cell Res) - "Here we show that the PARP-1/2/3 inhibitor AZD2461 in combination with the CHK1 inhibitor UCN-01 altered the DNA damage response and reduced cell proliferation in PEL cells, an aggressive B cell lymphoma highly resistant to chemotherapies. Finally, we found that the pharmacological or genetic inhibition of p21 counteracted the viral lytic cycle activation and further reduced PEL cell proliferation, suggesting that it could induce a double beneficial effect in this setting. This study unveils that, therapeutic approaches, based on the induction of DNA damage and the reduction of DNA repair, could be used to successfully treat this malignant lymphoma."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYC • RAD51

7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007) (clinicaltrials.gov) - P1; N=41; Completed; Sponsor: National Cancer Institute (NCI); Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Adenoid Cystic Carcinoma • Anal Carcinoma • Appendix Cancer • Basal Cell Carcinoma • Biliary Cancer • Breast Cancer • Carcinoid Tumor • Cervical Cancer • Cholangiocarcinoma • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gallbladder Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Germ Cell Tumors • Head and Neck Cancer • Hematological Malignancies • Hepatology • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hypopharyngeal Cancer • Laryngeal Cancer • Leiomyosarcoma • Lip Cancer • Liver Cancer • Lung Cancer • Lymphoma • Nasopharyngeal Carcinoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Non-melanoma Skin Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Otorhinolaryngology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Rectal Cancer • Salivary Gland Cancer • Sarcoma • Small Cell Lung Cancer • Small Intestinal Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • ER • HER-2 • PGR

7-hydroxystaurosporine and Topotecan Hydrochloride in Treating Patients With Relapsed or Progressed Small Cell Lung Cancer (clinicaltrials.gov) - P2; N=19; Completed; Sponsor: National Cancer Institute (NCI); Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

7-hydroxystaurosporine and Topotecan Hydrochloride in Treating Patients With Relapsed or Progressed Small Cell Lung Cancer (clinicaltrials.gov) - P2; N=37; Completed; Sponsor: National Cancer Institute (NCI); N=19 ➔ 37

Clinical • Combination therapy • Enrollment change • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Anticancer Effects of Herbal Medicine Compounds and Novel Formulations: a Literature Review. (PubMed, J Gastrointest Cancer) - "Considering side effects, toxicity, and higher costs of common cancer therapy approaches, application of novel herbal medicine-based therapies will confer promising insights for health outcomes."

Journal • Review • Gynecologic Cancers • Ovarian Cancer • Solid Tumor • CASP9 • FAS • TNFA

Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants. (PubMed, J Clin Immunol) - "Our assay facilitates a rapid and comprehensive assessment of the pathogenicity of MEFV variants and contributes to a refined definition of PAAD subtypes."

Journal • Dermatology • Genetic Disorders • Immunology • Inflammation • IL1B

Fast diagnostic test for familial Mediterranean fever based on a kinase inhibitor. (PubMed, Ann Rheum Dis) - "UCN-01-based inflammasome assays could be used to rapidly diagnose FMF, with high sensitivity and specificity."

Journal • Genetic Disorders • Immunology • Inflammation

Targeting dormant ovarian cancer cells in vitro and in an in vivo mouse model of platinum resistance. (PubMed, Mol Cancer Ther) - "UCN-01, a kinase inhibitor/mitochondrial uncoupler that has been shown to lead to Puma-induced mitochondrial apoptosis and ATP synthase inhibitor Oligomycin demonstrated effectiveness against spheroids, while spheroids were refractory to cisplatin and paclitaxel. Continued treatment with carboplatin was accompanied by an increase in tumor signal while there was little or no increase in tumor signal observed with subsequent treatment with UCN-01 or Oltipraz. Taken together, our findings suggest that genes involved in mitochondrial function in spheroids may be an important therapeutic target in preventing disease recurrence."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor

Protein kinase C inhibitors override ZEB1-induced chemoresistance in HCC. (PubMed, Cell Death Dis) - "Chemoresistant/mesenchymal HCC cells become addicted to PKC pathway and display sensitivity to PKC inhibitors such as UCN-01. Stratifying patients according to ZEB1 and combining UCN-01 with conventional chemotherapy may be an advantageous chemotherapeutic strategy."

Biomarker • Journal • Breast Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation - PMID: 23955575; "...UCN-01, a checkpoint kinase (Chk1) inhibitor, induced the relapse of G2/M arrest and radiosensitization of SQ20B-CSCs....The combination of ATRA and UCN-01 treatments with irradiation drastically decreased the surviving fraction at 2Gy of SQ20B-CSCs from 0.85 to 0.38 after photon irradiation, and from 0.45 to 0.21 in response to carbon ions."

Preclinical • Head and Neck Cancer • Oncology

Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01. (PubMed) - PLoS One - "In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments."

Journal • Biosimilar • Oncology