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DRUG CLASS:

GEF-H1 activator

Related drugs:
29d
Plinabulin in Combination With Radiation/Immunotherapy in Patients With Select Advanced Cancers After Progression on PD-1 or PD-L1 Targeted Antibodies (clinicaltrials.gov)
P1/2, N=19, Terminated, M.D. Anderson Cancer Center | Trial completion date: Jun 2025 --> Feb 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2025 --> Feb 2025; PI requested.
Trial completion date • Trial termination • Trial primary completion date
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MSI (Microsatellite instability)
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MSI-H/dMMR
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Keytruda (pembrolizumab) • Opdivo (nivolumab) • Tecentriq (atezolizumab) • Imfinzi (durvalumab) • Bavencio (avelumab) • plinabulin (BPI 2358)
2ms
Pembrolizumab in Combination with Plinabulin and Docetaxel for Metastatic NSCLC After ICIs (KeyPemls-004) (clinicaltrials.gov)
P2, N=47, Active, not recruiting, Peking Union Medical College Hospital | Recruiting --> Active, not recruiting
Enrollment closed
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Keytruda (pembrolizumab) • docetaxel • plinabulin (BPI 2358)
2ms
Diverse microtubule-destabilizing drugs induce equivalent molecular pathway responses in endothelial cells. (PubMed, bioRxiv)
Several MT-destabilizing drugs, including vinblastine, combretastatin A4, and plinabulin, are widely used, or are under evaluation for cancer treatment...To investigate whether differential modulation of molecular pathways might account for clinical differences, we compared gene expression and signaling pathway responses in human pulmonary microvascular endothelial cells (HPMECs), alongside the MT-stabilizing drug docetaxel and the pro-inflammatory cytokine TNF-α...This finding suggests that their distinct clinical effects are not caused by different effects on MTs, but rather by differences in drug transport, pharmacokinetics or tubulin isotype affinity. Our findings provide insights into how plinabulin might protect the bone marrow and may help medicinal chemists design MT drugs for new applications.
Journal
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TNFA (Tumor Necrosis Factor-Alpha)
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docetaxel • vinblastine • plinabulin (BPI 2358)
2ms
Dynamic Coupling of MAPK Signaling to the Guanine Nucleotide Exchange Factor GEF-H1. (PubMed, Onco Targets Ther)
Given that MAPK targeted therapies show limited clinical efficacy, highlights the need for novel targets. This review describes the unexpected complexity of GEF-H1 function leading to positive feedback that potentiates RAS-MAPK signaling and suggests inhibition of GEF-H1 as a therapeutic strategy for RAS-driven cancers.
Review • Journal
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KRAS (KRAS proto-oncogene GTPase) • RHOA (Ras homolog family member A) • RREB1 (Ras Responsive Element Binding Protein 1)
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KRAS mutation
2ms
Osteosarcoma biomarker analysis and drug targeting prediction based on pyroptosis-related genes. (PubMed, Medicine (Baltimore))
Our findings suggest potential mechanisms of action for 22 pyroptosis-related genes in osteosarcoma and preliminarily predicted that the occurrence of osteosarcoma is closely related to pyroptosis, apoptosis, and immune regulation. Predicted Triethyl phosphate, Plinabulin, Siltuximab as potential osteosarcoma treatments.
Journal
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TP53 (Tumor protein P53) • IL6 (Interleukin 6) • CASP3 (Caspase 3) • CASP8 (Caspase 8) • IL18 (Interleukin 18) • IL1A (Interleukin 1, alpha) • IL1B (Interleukin 1, beta)
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plinabulin (BPI 2358) • Sylvant (siltuximab)
5ms
Trial completion
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Opdivo (nivolumab) • Yervoy (ipilimumab) • plinabulin (BPI 2358)
5ms
Plinabulin in Combination With Radiation/Immunotherapy in Patients With Select Advanced Cancers After Progression on PD-1 or PD-L1 Targeted Antibodies (clinicaltrials.gov)
P1/2, N=19, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=12 --> 19
Enrollment closed • Enrollment change • Combination therapy • Metastases
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MSI (Microsatellite instability)
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MSI-H/dMMR
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Keytruda (pembrolizumab) • Opdivo (nivolumab) • Tecentriq (atezolizumab) • Imfinzi (durvalumab) • Bavencio (avelumab) • plinabulin (BPI 2358)
7ms
Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial. (PubMed, Lancet Respir Med)
Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population.
P3 data • Journal
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EGFR (Epidermal growth factor receptor)
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EGFR wild-type
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docetaxel • plinabulin (BPI 2358)
7ms
Phase I/II trial of plinabulin in combination with nivolumab and ipilimumab in patients with recurrent small cell lung cancer (SCLC): Big ten cancer research consortium (BTCRC-LUN17-127) study. (PubMed, Lung Cancer)
Plinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m2. While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected.
P1/2 data • Journal • Combination therapy
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PD-1 (Programmed cell death 1)
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Opdivo (nivolumab) • Yervoy (ipilimumab) • plinabulin (BPI 2358)
9ms
Regulation of the RhoA exchange factor GEF-H1 by pro-fibrotic stimuli through a positive feedback loop involving RhoA, MRTF and Sp1. (PubMed, Am J Physiol Cell Physiol)
MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. Since the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.
Journal
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TNFA (Tumor Necrosis Factor-Alpha) • RHOA (Ras homolog family member A) • TGFB1 (Transforming Growth Factor Beta 1)
10ms
Nivolumab in Combination With Plinabulin in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)
P1, N=18, Active, not recruiting, Lyudmila Bazhenova, M.D. | Trial completion date: Dec 2022 --> Jun 2025
Trial completion date • Combination therapy • Metastases
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Opdivo (nivolumab) • plinabulin (BPI 2358)
1year
BTCRC-LUN17-127: A Phase I/II Study of Nivolumab, Ipilimumab and Plinabulin in Patients With Recurrent Small Cell Lung Cancer (clinicaltrials.gov)
P1/2, N=39, Active, not recruiting, Salma Sabbour | Trial completion date: Jan 2024 --> Jul 2024
Trial completion date
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Opdivo (nivolumab) • Yervoy (ipilimumab) • plinabulin (BPI 2358)
1year
Phase classification • Combination therapy • Metastases
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MSI (Microsatellite instability)
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MSI-H/dMMR
|
Keytruda (pembrolizumab) • Opdivo (nivolumab) • Tecentriq (atezolizumab) • Imfinzi (durvalumab) • Bavencio (avelumab) • plinabulin (BPI 2358)
over1year
BTCRC-LUN17-127: A Phase I/II Study of Nivolumab, Ipilimumab and Plinabulin in Patients With Recurrent Small Cell Lung Cancer (clinicaltrials.gov)
P1/2, N=39, Active, not recruiting, Salma Sabbour | Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> Jan 2024
Enrollment closed • Trial completion date
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Opdivo (nivolumab) • Yervoy (ipilimumab) • plinabulin (BPI 2358)
over1year
Adding Plinabulin to pegfilgrastim to shorten neutropenia and improve quality of life peri-autologous hematopoietic cell transplant for multiple myeloma (IMW 2023)
Introduction: High dose melphalan with autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma is effective for disease control, but has a period of obligate neutropenia. The addition of plinabulin to pegfilgrastim did not add major toxicities after AHCT. Patients had elevated WBC on Day +2, low rates of NENF, and potentially less need for transfusion support. Plinabulin PK, quality of life data, and PROs will be presented.
HEOR
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CD34 (CD34 molecule)
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melphalan • plinabulin (BPI 2358) • Neulasta (pegfilgrastim)
over1year
Study of Plinabulin and Pegfilgrastim in People With Multiple Myeloma Undergoing an Autologous Hematopoietic Stem Cell Transplant (AHCT) (clinicaltrials.gov)
P2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025
Enrollment closed • Trial completion date • Trial primary completion date
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CD34 (CD34 molecule)
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plinabulin (BPI 2358) • Neulasta (pegfilgrastim)
over1year
Circular RNA circARHGEF28 inhibited the progression of prostate cancer via the miR-671-5p/LGALS3BP/NF-κB axis. (PubMed, Cancer Sci)
These results demonstrated that circARHGEF28 abolished the degradation of LGALS3BP by sponging miR-671-5p, thus blocking the activation of the NF-κB pathway. Our findings revealed that circARHGEF28/miR-671-5p/LGALS3BP/NF-κB may be an important axis that regulates PCa progression.
Journal
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LGALS3 (Galectin 3) • LGALS3BP (Lectin galactoside-binding soluble 3-binding protein) • MIR671 (MicroRNA 671)
almost2years
Study of Plinabulin and Pegfilgrastim in People With Multiple Myeloma Undergoing an Autologous Hematopoietic Stem Cell Transplant (AHCT) (clinicaltrials.gov)
P2, N=17, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024
Trial completion date • Trial primary completion date
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CD34 (CD34 molecule)
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plinabulin (BPI 2358) • Neulasta (pegfilgrastim)
almost2years
Design, synthesis and anti-tumor evaluation of plinabulin derivatives as potential agents targeting β-tubulin. (PubMed, Bioorg Med Chem Lett)
Compound 11c also significantly induced G2/M cell cycle arrest and apoptosis in dose dependent manner. These results suggest that compound 11c might be a potential candidate for cancer treatment as antimicrotubule agent.
Journal
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plinabulin (BPI 2358)
almost2years
Trial primary completion date
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Opdivo (nivolumab) • Yervoy (ipilimumab) • plinabulin (BPI 2358)
almost2years
HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1. (PubMed, Cell Death Dis)
Clinically, the levels of both HUNK expression and phosphorylation S645 of GEH-H1 are not only downregulated in CRC tissues with metastasis compared with that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of HUNK kinase direct phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.
Journal
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RHOA (Ras homolog family member A)
almost2years
Mechanism-based peripheral blood biomarkers to evaluate anticancer effects of the plinabulin/docetaxel combination (plin/doc) vs. doc alone in second/third line EGFR wild-type (WT) NSCLC. (ASCO 2023)
Bone marrow suppression remains a common serious risk of classical/non-classical cancer drugs. Under these conditions, the addition of Plin offers rapid protection of GMP lineage cells which can be captured by simple blood cell counts. Incorporation of blood-based biomarkers may help enrich NSCLC pts with better sensitivity to Plin/Doc combination than Doc alone.
EGFR (Epidermal growth factor receptor)
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EGFR wild-type
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docetaxel • plinabulin (BPI 2358)
almost2years
Pembrolizumab in Combination With Plinabulin and Docetaxel For Metastatic NSCLC After ICIs (KeyPemls-004) (clinicaltrials.gov)
P2, N=47, Recruiting, Peking Union Medical College Hospital | Not yet recruiting --> Recruiting | Initiation date: Nov 2022 --> Feb 2023
Enrollment open • Trial initiation date • Combination therapy • Metastases
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Keytruda (pembrolizumab) • docetaxel • plinabulin (BPI 2358)
2years
ARHGEF2 regulates lineage plasticity promoting neuroendocrine differentiation and treatment resistance in advanced prostate Cancer (AUA 2023)
Our studies suggest that ARHGEF2 activation promotes neural lineage plasticity contributing to the survival and proliferation of enzalutamide-resistance and NEPC cells. ARHGEF2 could serve as a biomarker to stratify advanced prostate cancer patients for better treatment options and a potential therapeutic target in advanced prostate cancer.
Metastases
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AR (Androgen receptor) • SYP (Synaptophysin) • CHGA (Chromogranin A)
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Xtandi (enzalutamide)
2years
Study protocol of KeyPemls-004: A phase 2 study of pembrolizumab in combination with plinabulin and docetaxel in previously treated patients with metastatic non-small cell lung cancer and progressive disease (PD) after immunotherapy (PD-1/PD-L1 inhibitor) alone or in combination with platinum-doublet chemotherapy. (PubMed, Thorac Cancer)
This trial will provide evidence of the benefit and safety of pembrolizumab in combination with plinabulin and docetaxel in metastatic NSCLC patients who have been exposed and developed resistance to first-line PD-1/PD-L1 inhibitor either as monotherapy or in combination with chemotherapy.
Clinical protocol • P2 data • Journal • Combination therapy • Metastases
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase)
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EGFR wild-type • ALK wild-type
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Keytruda (pembrolizumab) • docetaxel • plinabulin (BPI 2358)
over2years
Construction of a combined random forest and artificial neural network diagnosis model to screening potential biomarker for hepatoblastoma. (PubMed, Pediatr Surg Int)
These 5 candidate genes contribute to the molecular diagnosis and targeted therapy of HB. And we found "ARHGEF2-RhoA-Cyclin D1/CDK4/CDK6-EF2" is a key mechanism regulating cell cycle pathway in HB. This will be helpful in the treatment of HB. The occurrence of HB is related to abnormal TIICs. We speculated that memory B cells play an important role in HB.
Journal
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CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • CDK6 (Cyclin-dependent kinase 6) • RHOA (Ras homolog family member A) • TCF3 (Transcription Factor 3) • STMN1 (Stathmin 1)
over2years
Androgen deprivation restores ARHGEF2 to promote neuroendocrine differentiation of prostate cancer. (PubMed, Cell Death Dis)
Correspondingly, AR inhibition or AR antagonist treatment can restore ARHGEF2 expression, thereby allowing prostate cancer cells to induce treatment resistance and tolerance. Overall, our findings provide an explanation for the contradictory clinical results that ADT resistance may be caused by the up-regulation of ARHGEF2 and provide a novel target.
Journal
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AR (Androgen receptor)
over2years
New P2 trial • Combination therapy • Metastases
|
EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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Keytruda (pembrolizumab) • docetaxel • plinabulin (BPI 2358)
over2years
Targeted RNA-Based NGS Significantly Enhanced the Proportion of Druggable Patients in Melanoma (AMP 2022)
To fully reveal targetable gene fusions or oncogenic isoforms in melanoma, targeted RNA-based NGS can be used as a supplement to DNA-based NGS testing.
Clinical • Next-generation sequencing
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BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • FGFR1 (Fibroblast growth factor receptor 1) • ETV6 (ETS Variant Transcription Factor 6) • KDM6A (Lysine Demethylase 6A) • AGK (Acylglycerol Kinase) • NSD3 (Nuclear Receptor Binding SET Domain Protein 3) • TACC1 (Transforming Acidic Coiled-Coil Containing Protein 1) • ZKSCAN1 (Zinc Finger With KRAB And SCAN Domains 1)
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ALK positive • ALK fusion • FGFR1 fusion
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Onco PanScan™
over2years
Activation of neural lineage networks and ARHGEF2 in enzalutamide-resistant and neuroendocrine prostate cancer and association with patient outcomes. (PubMed, Commun Med (Lond))
Furthermore, downregulation of ARHGEF2 gene expression suppresses cell viability and markers of neuroendocrine differentiation in enzalutamide-resistant and neuroendocrine cells. The 95 neural lineage gene signatures capture an early molecular shift toward neuroendocrine differentiation, which could stratify advanced prostate cancer patients to optimize clinical treatment and serve as a source of potential therapeutic targets in advanced prostate cancer.
Journal
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AR (Androgen receptor) • EPHB2 (EPH Receptor B2) • SYP (Synaptophysin) • CHGA (Chromogranin A)
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Xtandi (enzalutamide)
over2years
DUBLIN-3: Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC (clinicaltrials.gov)
P3, N=559, Completed, BeyondSpring Pharmaceuticals Inc. | Active, not recruiting --> Completed
Trial completion
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase)
|
EGFR L858R • EGFR exon 19 deletion • ALK rearrangement
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docetaxel • plinabulin (BPI 2358)
over2years
Metastatic Merkel Cell Carcinoma Presenting as Silent Infiltrative Liver Disease: A Lesson Emphasizing the Utility of Liver Biopsy in the Exclusion of Immune Checkpoint Inhibitor-Mediated Hepatotoxicity (ACG 2022)
He was started on a treatment regimen of pembrolizumab and plinabulin (a phase I microtubule inhibitor) with radiation to the liver 2 months ago...After an initial period of observation, the patient was started on oral budesonide 9 mg/d and ursodiol 1000 mg/d for empiric treatment of IMH without subsequent improvement in liver enzymes...At the end of treatment, transaminases reached >5 times ULN. No improvement was seen in liver enzymes after initiating empiric steroid therapy for suspected IMH.
Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker
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KRT20 (Keratin 20) • SYP (Synaptophysin)
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Keytruda (pembrolizumab) • plinabulin (BPI 2358)
over2years
Plinabulin after autologous hematopoietic cell transplant to decrease duration of neutropenia and improve quality of life peri-transplant (IMW 2022)
In this pilot trial (NCT05130827, a single dose of 40mg of intravenous plinabulin was given on day of stem cell infusion (Day 0) in conjunction with pegfilgrastim on Day +1 after high dose melphalan and AHCT with the primary objective to reduce the period of absolute neutropenia in patients with MM. To date, plinabulin appears well tolerated, and patients have not had non-engraftment related neutropenic fevers. Enrollment is ongoing, and full trial results will be presented.
HEOR
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CD34 (CD34 molecule)
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melphalan • plinabulin (BPI 2358) • Neulasta (pegfilgrastim)
over2years
ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation. (PubMed, Cell Death Dis)
HCC cell growth was more inhibited when ARHGEF2 knockdown was paired with targeted medicines. Collectively, we uncovered a previously hidden mechanism where ARHGEF2/EDN1 pathway promotes angiogenesis and participates in ER stress-related drug resistance in HCC.
Journal
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ZNF263 (Zinc finger protein 263)
almost3years
Subgroup analysis in patients (pts) with non-squamous (N-Sq), EGFR-wild type (wt), second/third-line NSCLC from the global phase (Ph) 3 trial DUBLIN-3 (BPI-2358-103) with the plinabulin/docetaxel (Plin/Doc) combination versus Doc alone. (ASCO 2022)
The addition of Plin to Doc was superior to SoC Doc alone for efficacy and safety in the clinically relevant subgroup of non-squamous EGFR-wild type, 2nd/3rd line NSCLC pts.
Clinical
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EGFR (Epidermal growth factor receptor)
|
EGFR wild-type
|
docetaxel • plinabulin (BPI 2358)
almost3years
DUBLIN-3 results on quality of life (QoL) in second/third-line EGFR-wild type NSCLC patients (pts) receiving docetaxel (Doc) with or without plinabulin (Plin) using the validated EORTC QLQ C30 and QLQ LC13 questionnaires. (ASCO 2022)
We previously reported an OS, Safety, and QTWiST benefit with Plin/Doc vs Doc alone (ESMO 2021) in EGFR wild type 2nd/3rd line NSCLC pts from DUBLIN-3. Here, we report statistically significant QoL benefits with Plin/Doc vs Doc alone, as assessed with EORTC QLQ C30 and LC13, which may be relevant to guide treatment decisions in this generally sick patient population.
Clinical • HEOR
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EGFR (Epidermal growth factor receptor)
|
EGFR wild-type
|
docetaxel • plinabulin (BPI 2358)
almost3years
An innovative prognostic model based on autophagy-related long noncoding RNA signature for low-grade glioma. (PubMed, Mol Cell Biochem)
In addition, the lncRNA signature was independently prognostic and potentially associated with the progression of LGG. Therefore, the 9-autophagy-related-lncRNA signature may play a crucial role in the diagnosis and treatment of LGG, which may offer new avenues for tumour-targeted therapy.
Journal
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PSMB8 (Proteasome 20S Subunit Beta 8)
over3years
N6-methyladenosine reader YTHDF1 promotes ARHGEF2 translation and RhoA signaling in colorectal cancer. (PubMed, Gastroenterology)
We identify a novel oncogenic epitranscriptome axis of YTHDF1-mA-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC.
Journal
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RHOA (Ras homolog family member A) • YTHDF1 (YTH N6-Methyladenosine RNA Binding Protein 1)
over3years
Enrollment open
|
CD34 (CD34 molecule)
|
plinabulin (BPI 2358) • Neulasta (pegfilgrastim)
over3years
New P2 trial
|
CD34 (CD34 molecule)
|
plinabulin (BPI 2358) • Neulasta (pegfilgrastim)
over3years
The RhoA dependent anti-metastatic function of RKIP in breast cancer. (PubMed, Sci Rep)
Here we show that RKIP inhibits cancer cell invasion and metastasis by stimulating RhoA anti-tumorigenic functions. Mechanistically, RKIP activates RhoA in an Erk2 and GEF-H1 dependent manner to enhance E-cadherin membrane localization and inhibit CCL5 expression.
Journal
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CDH1 (Cadherin 1) • CCL5 (Chemokine (C-C motif) ligand 5) • MAPK1 (Mitogen-activated protein kinase 1) • RHOA (Ras homolog family member A)