^
Contact us  to learn more about
our Premium Content:  News alerts, weekly reports and conference planners
DRUG CLASS:

Heat shock factor 1 inhibitor

Related drugs:
2d
NCI-2018-01928: CBL0137 in Treating Patients With Advanced Extremity Melanoma or Sarcoma (clinicaltrials.gov)
P1, N=7, Terminated, Roswell Park Cancer Institute | N=36 --> 7 | Trial completion date: Aug 2024 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2024 --> Jan 2024; low accrual
Enrollment change • Trial completion date • Trial termination • Trial primary completion date • Metastases
5d
Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor. (PubMed, Biochem Pharmacol)
Furthermore, the combination treatment inhibits tumor growth and AKT signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/AKT signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • CASP3 (Caspase 3) • CDK1 (Cyclin-dependent kinase 1) • CCNB1 (Cyclin B1) • HSF1 (Heat Shock Transcription Factor 1)
|
danusertib (PHA-739358)
5ms
Heat Shock Factor 1 Inhibition: A Novel Anti-Cancer Strategy with Promise for Precision Oncology. (PubMed, Cancers (Basel))
With its important roles in tumorigenesis and tumor progression, targeting HSF1 offers a novel cancer treatment strategy. In this article, we examine the basic function of HSF1 and its regulatory mechanisms, focus on the mechanisms involved in HSF1's roles in different cancer types, and examine current HSF1 inhibitors as novel therapeutics to treat cancers.
Review • Journal
|
HSF1 (Heat Shock Transcription Factor 1)
5ms
HSF1 inhibits antitumor immune activity in breast cancer by suppressing CCL5 to block CD8+ T cell recruitment. (PubMed, Cancer Res)
HSF1 suppressed expression of CCL5, a chemokine for CD8+ T cells, and upregulation of CCL5 upon HSF1 loss significantly contributed to the recruitment of CD8+ T cells. These findings indicate that HSF1 suppresses antitumor immune activity by reducing CCL5 to limit CD8+ T cell homing to breast tumors and prevent immune-mediated destruction, which has implications for the lack of success of immune modulatory therapies in breast cancer.
Journal
|
CD8 (cluster of differentiation 8) • CCL5 (Chemokine (C-C motif) ligand 5) • HSF1 (Heat Shock Transcription Factor 1)
10ms
Inhibition of Triple-Negative Breast Cancer Growth in a Mouse Model – Enhancement of Modulated Electro-Hyperthermia (mEHT) Effects by Heat Shock Factor 1 Inhibition (EACR 2023)
Immunohistochemistry confirmed the molecular data. Combined therapy of mEHT and KRIBB11 significantly reduced tumor weight (160.3 mg ± 33.26 mg) further compared to monotherapy (mEHT: 236.8 mg ± 46.42 mg; KRIBB11: 312.3 mg ± 41.45 mg).ConclusionCombined mEHT-therapy with HSF1 inhibition can be a possible new strategy of treating TNBC with a great translational potential.
Preclinical
|
HSF1 (Heat Shock Transcription Factor 1)
11ms
HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies. (PubMed, J Med Chem)
Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian cancer and other malignancies.
Journal
|
HSF1 (Heat Shock Transcription Factor 1)
|
NXP800
12ms
A Phase 1 Clinical Study of NXP800 in Subjects With Advanced Cancers and Expansion in Subjects With Ovarian Cancer (clinicaltrials.gov)
P1, N=61, Recruiting, Nuvectis Pharma, Inc. | N=17 --> 61 | Trial completion date: Apr 2023 --> Jun 2025 | Trial primary completion date: Jan 2023 --> Dec 2024
Enrollment change • Trial completion date • Trial primary completion date • Metastases
|
ARID1A (AT-rich interaction domain 1A) • BRCA (Breast cancer early onset)
|
ARID1A mutation • BRCA mutation
|
NXP800
1year
Activation of the integrated stress response by the developmental HSF1 pathway inhibitor NXP800 (AACR 2023)
Using an siRNA approach to determine if activation of the ISR components was contributing to growth inhibition following NXP800 exposure, we found that blocking the induction of ATF4 reduced the response of NXP800-sensitive SK-OV-3 human ovarian carcinoma cells to NXP800 treatment.In summary, NXP800 acts on cancer cells to induce activation of the ISR pathway via GCN2, which then leads to inhibition of HSF1 activation. Further studies are underway to determine the precise molecular target of NXP800 and the mechanism of HSF1 pathway inhibition.
Late-breaking abstract
|
ATF4 (Activating Transcription Factor 4) • CHAC1 (ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1) • HSF1 (Heat Shock Transcription Factor 1)
|
NXP800
1year
Inhibition of HSF1 demonstrates therapeutic efficacy in preclinical models of cholangiocarcinoma (AACR 2023)
NXP800, a HSF1 inhibitor, demonstrated significant therapeutic activity in a cholangiocarcinoma PDX. Further studies are needed and being performed to determine the role of HSF1 inhibition in human cholangiocarcinoma.
Preclinical • Tumor mutational burden
|
TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR1 (Fibroblast growth factor receptor 1) • AR (Androgen receptor) • ARID1A (AT-rich interaction domain 1A) • HSF1 (Heat Shock Transcription Factor 1)
|
NRAS mutation • ARID1A mutation • FGFR2 mutation • FGFR1 mutation • NRAS Q61 • AR overexpression • FGFR2 overexpression • AR expression • FGFR2 expression
|
NXP800
1year
Dual inhibition of HSF1 and DYRK2 impedes cancer progression. (PubMed, Biosci Rep)
Furthermore, targeting the DYRK2-HSF1 axis induces death in proteasome inhibitor resistant cells and reduces triple-negative breast cancer burden in ectopic and orthotopic xenograft models. Together the data indicate that co-targeting of kinase DYRK2 and its substrate HSF1 could prove to be a beneficial strategy in perturbing neoplastic malignancies.
Journal
|
HSF1 (Heat Shock Transcription Factor 1)
over1year
NXP800 versus cisplatin in ARID1a-mutated Ovarian Clear Cell Carcinoma xenograft models (ESMO-GC 2023)
Planned phase 1b expansion cohorts will include ovarian clear cell carcinoma and ovarian endometrioid carcinoma patients with ARID1A mutation. Legal entity responsible for the study The authors.
Preclinical
|
ARID1A (AT-rich interaction domain 1A) • HSF1 (Heat Shock Transcription Factor 1)
|
ARID1A mutation
|
cisplatin • NXP800
over1year
HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia. (PubMed, Nat Commun)
Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML.
Journal
|
SDHC (Succinate Dehydrogenase Complex Subunit C) • HSF1 (Heat Shock Transcription Factor 1)
over1year
Discovery and validation of biomarkers to support clinical development of NXP800: A first-in-class orally active, small-molecule HSF1 pathway inhibitor (AACR-NCI-EORTC 2022)
Conclusions A Phase 1 trial (NCT05226507) of NXP800 is underway, incorporating the validated predictive, PK and PD biomarkers that constitute a Pharmacological Audit Trail. Future expansion cohorts will include patients with ARID1A mutation, including ovarian clear cell carcinoma and ovarian endometrioid carcinoma.
Clinical
|
ARID1A (AT-rich interaction domain 1A) • ATF4 (Activating Transcription Factor 4) • ATF3 (Activating Transcription Factor 3) • HSF1 (Heat Shock Transcription Factor 1)
|
ARID1A mutation
|
NXP800
over1year
CBL0137 for the Treatment of Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma (clinicaltrials.gov)
P1/2, N=38, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting
Enrollment closed
|
AFP (Alpha-fetoprotein)
|
CBL137 IV
almost2years
Heat shock factor 1 inhibition sensitizes pancreatic cancer to gemcitabine via the suppression of cancer stem cell-like properties. (PubMed, Biomed Pharmacother)
Our study reveals a novel mechanism in which HSF1 promotes the chemoresistance of pancreatic cancer to gemcitabine by modulating CSC-like properties. Targeting HSF1 could be thus a rational strategy to improve treatment outcomes.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PDX1 (Pancreatic And Duodenal Homeobox 1) • HSF1 (Heat Shock Transcription Factor 1)
|
gemcitabine
2years
CBL0137 for the Treatment of Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma (clinicaltrials.gov)
P1/2, N=38, Recruiting, Children's Oncology Group | Not yet recruiting --> Recruiting | Trial primary completion date: Feb 2026 --> Dec 2026
Enrollment open • Trial primary completion date
|
AFP (Alpha-fetoprotein)
|
CBL137 IV
2years
Mechanism of miR-455-3 in suppressing epithelial-mesenchymal transition and angiogenesis of non-small cell lung cancer cells. (PubMed, Cell Stress Chaperones)
HSF1 can interact with GLS1 and elevate the expression of GLS1. GLS1 can partially abolish the suppressive effect of miR-455-3p in NSCLC cells.miR-455-3p can bind HSF1 to suppress the GLS1 in NSCLC cells, therefore suppressing EMT progression and angiogenesis of NSCLC cells.
Journal
|
CDH1 (Cadherin 1) • VIM (Vimentin)
|
CDH1 expression
2years
CBL0137 for the Treatment of Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma (clinicaltrials.gov)
P1/2, N=38, Not yet recruiting, Children's Oncology Group | Trial primary completion date: Dec 2026 --> Feb 2026
Trial primary completion date
|
AFP (Alpha-fetoprotein)
|
CBL137 IV
over2years
FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an mA-YTHDF2-dependent manner. (PubMed, Mol Ther)
FTO inhibition, especially when combined with bortezomib treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcil2rg/Nju (NCG) mice. We demonstrated the functional importance of mA demethylase FTO in MM progression, especially in promoting extramedullary myeloma formation and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.
Journal
|
FTO (Alpha-Ketoglutarate-Dependent Dioxygenase FTO) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit)
|
bortezomib
over2years
PLOD1 acts as a tumor promoter in glioma via activation of the HSF1 signaling pathway. (PubMed, Mol Cell Biochem)
High expression of PLOD1 can increase the proliferation and colony formation of U87 cells by activating the HSF1 signaling pathway. This study suggested PLOD1/HSF1 as an effective therapeutic target for gliomas.
Journal
|
BIRC5 (Baculoviral IAP repeat containing 5)
|
BIRC5 expression
over2years
Targeting of HSP70/HSF1 Axis Abrogates In Vitro Ibrutinib-Resistance in Chronic Lymphocytic Leukemia. (PubMed, Cancers (Basel))
We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients.
Preclinical • Journal
|
PLCG2 (Phospholipase C Gamma 2)
|
Imbruvica (ibrutinib)
over2years
The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells. (PubMed, Cell Death Discov)
NCT-58 treatment suppressed growth and angiogenesis in a trastuzumab-resistant xenograft model, concomitant with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90. These findings warrant further investigation of NCT-58 to address trastuzumab resistance in heterogeneous HER2-positive cancers.
Journal
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 positive
|
Herceptin (trastuzumab)
over2years
CBL0137 for the Treatment of Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma (clinicaltrials.gov)
P1/2, N=38, Not yet recruiting, Children's Oncology Group | Initiation date: Sep 2021 --> Dec 2021
Clinical • Trial initiation date
|
AFP (Alpha-fetoprotein)
|
CBL137 IV
over2years
KRIBB11 Induces Apoptosis in A172 Glioblastoma Cells via MULE-Dependent Degradation of MCL-1. (PubMed, Molecules)
In conclusion, stabilization of MULE upon KRIBB11 treatment is apparently an essential step for degradation of MCL-1 and the subsequent induction of apoptosis in A172 cells. Our results have expanded the knowledge on molecular pathways controlled by KRIBB11 and could be potentially effective for developing an inhibitory therapeutic strategy for glioblastoma.
Journal
|
MCL1 (Myeloid cell leukemia 1)
over2years
Bioactive Hexapeptide Reduced the Resistance of Ovarian Cancer Cells to DDP by Affecting HSF1/HSP70 Signaling Pathway. (PubMed, J Cancer)
Pifithrin-μ (PFTμ, HSP70 inhibitor) decreased or removed the effects of peptide in increasing the sensitivity of ovarian cancer cells to DDP. This suggests that PGPIPN enhanced the sensitivity of ovarian cancer cells to DDP partially via reducing the activity of HSF1/HSP70 signaling pathway, thus inducing cell apoptosis and decreasing repairment of DNA damage.
Journal
|
ABCB1 (ATP Binding Cassette Subfamily B Member 1) • ERCC1 (Excision repair cross-complementation group 1)
over2years
A standardized extract of Asparagus officinalis stem improves HSP70-mediated redox balance and cell functions in bovine cumulus-granulosa cells. (PubMed, Sci Rep)
Furthermore, EAS significantly increased progesterone synthesis. Thus, EAS improves HSP70-mediated redox balance and cell function in bovine CG cells.
Journal
|
KEAP1 (Kelch Like ECH Associated Protein 1) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
|
KEAP1 expression
over2years
VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines. (PubMed, Cancer Sci)
VLX1570 increased the amount of high molecular weight polyubiquitinated proteins and the expression of HSP70 as the result of the suppression of ubiquitine proteasome system, the expression of heme oxygenase-1 and the amount of phosphorylation in JNK and p38 associated with the generation of reactive oxygen species (ROS) induced apoptosis and the amount of phosphorylation in eIF2α, inducing the expression of ATF4 and endoplasmic reticulum (ER) stress dependent apoptosis protein, CHOP and the amount of phosphorylation slightly in IRE1α, leading to increased expression of XBP-1s in leukemia cell lines. In the present study, we demonstrate that VLX1570 induces apoptosis and exerts a potential anti-leukemic effect through the generation of ROS and induction of ER stress in leukemia cell lines.
Preclinical • Journal
|
HMOX1 (Heme Oxygenase 1) • ATF4 (Activating Transcription Factor 4)
|
HMOX1 expression
|
VLX1570
over2years
Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response. (PubMed, Cancers (Basel))
Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response.
Journal
|
LDHA (Lactate dehydrogenase A) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
over2years
Anticancer Effects of Cinnamaldehyde through Inhibition of ErbB2/HSF1/LDHA Pathway in 5637 Cell Line of Bladder Cancer. (PubMed, Anticancer Agents Med Chem)
Thus, Cinnamaldehyde induced apoptosis and decreased growth in 5637 cells by reducing ErbB2-HSF1-LDHA pathway.
Preclinical • Journal
|
HER-2 (Human epidermal growth factor receptor 2) • LDHA (Lactate dehydrogenase A)
|
HER-2 expression
over2years
Prevention of High Glucose-Mediated EMT by Inhibition of Hsp70 Chaperone. (PubMed, Int J Mol Sci)
Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.
Journal
|
CDH1 (Cadherin 1) • SNAI2 (Snail Family Transcriptional Repressor 2)
over2years
Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity. (PubMed, Nat Commun)
In p53 tumors WTp53 activation by constitutive stress represses MLK3, thereby weakening the MAPK-HSF1 response necessary for tumor survival. This creates selection pressure for p53LOH which eliminates the repressive WTp53-MAPK-HSF1 axis and unleashes tumor-promoting HSF1 functions, inducing mutp53 stabilization enabling invasion.
Journal
|
CDKN1A (Cyclin-dependent kinase inhibitor 1A) • MAP3K11 (Mitogen-Activated Protein Kinase Kinase Kinase 11)
|
TP53 mutation
over2years
Identification of a heat-inducible novel nuclear body containing the long noncoding RNA MALAT1. (PubMed, J Cell Sci)
The formation of HiNoCo body is reversible and independent of heat shock factor 1, the master transcription regulator of the heat-shock response. Our results suggest the HiNoCo body participates in heat shock factor 1-independent heat-shock responses in mammalian cells.
Journal
|
MALAT1 (Metastasis associated lung adenocarcinoma transcript 1)
over2years
Targeting HSF1 as a Therapeutic Strategy for Multiple Mechanisms of EGFR Inhibitor Resistance in EGFR Mutant Non-Small-Cell Lung Cancer. (PubMed, Cancers (Basel))
We generated erlotinib-resistant HCC827-ErlR cells, which showed resistance to erlotinib, gefitinib, osimertinib, and doxorubicin. Finally, we demonstrated the efficacy of the HSF1 inhibitor on PC9-ErlR cells expressing mutant EGFR (T790M) in vivo. Collectively, these findings support a targetable HSF1-(HSP90/HSP70/BAG3)-(BCL2/MCL1/EGFR/MET/AXL) pathway to overcome multiple mechanisms of EGFR-TKI resistance.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • AXL (AXL Receptor Tyrosine Kinase) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
|
EGFR mutation • EGFR T790M • MCL1 expression
|
Tagrisso (osimertinib) • erlotinib • gefitinib • doxorubicin hydrochloride
over2years
Combined inhibition of AURKA and HSF1 suppresses proliferation and promotes apoptosis in hepatocellular carcinoma by activating endoplasmic reticulum stress. (PubMed, Cell Oncol (Dordr))
Combined inhibition of AURKA and HSF1 shows an excellent anti-tumor effect on HCC cells in vitro and in vivo, which may be mediated by ERS. These findings suggest that both AURKA and HSF1 may serve as targets for HCC treatment.
Journal
|
AURKA (Aurora kinase A) • ATF4 (Activating Transcription Factor 4)
|
danusertib (PHA-739358)
almost3years
The HSF1/miR-135b-5p axis induces protective autophagy to promote oxaliplatin resistance through the MUL1/ULK1 pathway in colorectal cancer. (PubMed, Oncogene)
These results indicated that miR-135b-5p upregulation in colorectal cancer could induce protective autophagy through the MUL1/ULK1 signaling pathway and promote oxaliplatin resistance. Targeting miR-135b-5p may provide a new treatment strategy for reversing oxaliplatin resistance in CRC.
Journal
|
MIR135B (MicroRNA 135b)
|
oxaliplatin
almost3years
Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML. (PubMed, Leukemia)
Consistently, the combination of RHT and FLT3 inhibitors was highly synergistic in primary FLT3-mutated AML cells. Our results provide a novel therapeutic rationale for co-targeting eIF4A and FLT3 to address the clinical challenge of treating FLT3-mutant AML.
Review • Journal
|
FLT3 (Fms-related tyrosine kinase 3) • EIF4G1 (Eukaryotic translation initiation factor 4 gamma, 1)
|
FLT3 mutation
almost3years
Heme oxygenase-1 induction by heat shock in rat hepatoma cell line is regulated by the coordinated function of HSF1, NRF2, AND BACH1. (PubMed, J Biochem)
These observations indicate that HO-1 induction by HS is mainly mediated by HSF1 binding to the proximal HSE. NRF2 binding to MARE by HS is predominantly suppressed by an increased binding of BACH1.
Preclinical • Journal
|
BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • HMOX1 (Heme Oxygenase 1) • BACH1 (BTB Domain And CNC Homolog 1)
almost3years
ΔN63 suppresses the ability of pregnancy-identified mammary epithelial cells (PIMECs) to drive HER2-positive breast cancer. (PubMed, Cell Death Dis)
In addition, scRNA-seq revealed upregulation of several cancer-associated (Il-4/Il-13, Hsf1/HSP), oncogenic (TGFβ, NGF, FGF, MAPK) and self-renewal (Wnt, Notch) pathways in p63+/-;ErbB2 luminal cells and PIMECs per se. Altogether, these data reveal a complex role of p63 in PIMECs and pregnancy-associated HER2+ BC: maintaining the amount of PIMECs while suppressing their intrinsic tumorigenic capacity.
Journal
|
HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • TGFB1 (Transforming Growth Factor Beta 1) • TP63 (Tumor protein 63) • IL4 (Interleukin 4)
|
HER-2 positive • HR positive • HER-2 amplification