- |||||||||| Ibrance (palbociclib) / Pfizer, ulixertinib (BVD-523) / BioMed Valley Discoveries
Trial completion date, Trial primary completion date, Combination therapy, Metastases: Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors (clinicaltrials.gov) - Nov 9, 2022
P1, N=45, Active, not recruiting,
Trial completion date: Oct 2023 --> Apr 2026 | Trial primary completion date: Oct 2022 --> Jul 2024
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, ulixertinib (BVD-523) / BioMed Valley Discoveries
RAF-Independent MEK Mutations Drive Histiocytic Neoplasms In Vivo and Are Sensitive to Single-Agent ERK Inhibition in Patients (ENMCC - 275-277) - Nov 4, 2022 - Abstract #ASH2022ASH_3431;
Importantly, this molecular entity is resistant to MEK inhibition in some patients, a phenomenon previously undocumented, but responsive to ERK inhibition, which may be a promising therapeutic approach to histiocytic neoplasms unresponsive to allosteric MEK inhibition. The clinical observation of efficacy of ERK inhibition in MEK inhibitor resistant histiocytoses patients has resulted in a soon-to-be initiated focused phase 2 clinical trial of ulixertinib in adults with histiocytoses.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Journal: Identifying novel putative ERK1/2 inhibitors via hybrid scaffold hopping -FBDD approach. (Pubmed Central) - Aug 31, 2022
In this study, Ulixertinib, a known ERK2 inhibitor was selected to perform scaffold hopping to discover new scaffolds with similar binding mode followed by molecular docking analysis of the hits with highest similarity score to determine, both the binding mode and affinity in the catalytic domain of ERK2...Overall, 3 hits (ligand 6, 8 and 10) were found to possess optimum pharmacodynamic and pharmacokinetic profile, in-silico, to be claimed as putative ERK2 inhibitors. This study disclosed new lead molecules with putative ERK2 inhibitory potential which may be further validated via biological evaluation.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Journal: Case report: response to the ERK1/2 inhibitor ulixertinib in BRAF D594G cutaneous melanoma. (Pubmed Central) - Jul 6, 2022
We report the case of an individual diagnosed with stage III BRAF D594G-mutant melanoma who experienced an extraordinary response to the ERK1/2 inhibitor ulixertinib as fourth-line therapy. Ulixertinib was obtained via an intermediate expanded access protocol with unique flexibility to permit both single-agent and combination treatments, dose adjustments, breaks in treatment to undergo surgery, and long-term preventive treatment following surgical resection offering this patient the potential for curative treatment.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Enrollment open, Combination therapy, Pan tumor, Metastases: Trial of Ulixertinib in Combination With Hydroxychloroquine in Patients With Advanced Gastrointestinal (GI) Malignancies (clinicaltrials.gov) - Jun 29, 2022
P2, N=215, Recruiting,
Ulixertinib was obtained via an intermediate expanded access protocol with unique flexibility to permit both single-agent and combination treatments, dose adjustments, breaks in treatment to undergo surgery, and long-term preventive treatment following surgical resection offering this patient the potential for curative treatment. Not yet recruiting --> Recruiting
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Sleeping beauty mutagenesis screens identify genes required for primary and metastatic breast cancer in cooperation with p53- versus p53:Rb-loss (Poster Area) - Jun 28, 2022 - Abstract #EACR2022EACR_996;
Finally, inhibition of ERK1/2 of Ras-Raf-MAPK pathway by ulixertinib (a potent ERK1/2 inhibitor) suppressed growth of BL/TN breast cancer cell lines with high Ras activity which also carry TP53 and RB1 alterations...Conclusion These results suggest that genes involved in Ras pathway activation may promote metastatic p53:Rb -deficient TN breast cancer. Hence, therapeutic modalities such as ERK1/2 inhibitors may serve as potential therapeutic intervention against this metastatic TNBC subgroup.
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte, Nplate (romiplostim) / Amgen, Kyowa Kirin, ulixertinib (BVD-523) / BioMed Valley Discoveries
ERK1/2 INHIBITION REDUCES OSTEOPONTIN PLASMA LEVELS AND BONE MARROW FIBROSIS IN A MYELOFIBROSIS MOUSE MODEL () - May 13, 2022 - Abstract #EHA2022EHA_2117;
Moreover, in a MF mouse model, the concurrent inhibition of ERK1/2 and JAK2 signaling pathways displayed synergistic effects by diminishing OPN plasma levels and constraining BM fibrosis. These results provide a rational for the development of novel combination therapeutic approach for PMF patients.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Biomarker, Enrollment change, Trial primary completion date, Metastases: Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - Apr 7, 2022
P2, N=20, Active, not recruiting,
These results confirm the possibility of targeting different elements of the MAPK and MTOR pathways to increase the response for NF1-mutated sarcomas. N=49 --> 20 | Trial primary completion date: Mar 2023 --> Mar 2022
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Biomarker, Trial completion date, Trial primary completion date, Metastases: Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - Apr 4, 2022
P2, N=49, Active, not recruiting,
N=49 --> 20 | Trial primary completion date: Mar 2023 --> Mar 2022 Trial completion date: Mar 2022 --> Mar 2023 | Trial primary completion date: Mar 2022 --> Mar 2023
- |||||||||| Pancreatic cancer enhances HER2 signaling through DUSP6 to circumvent therapeutic MAPK inhibition (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6810;
We demonstrated that the combination of MEK or ERK inhibitor plus DS-8201a is extremely effective, leading to complete tumor regression in multiple PDAC PDX models. This combination should be advanced as a clinical trial for PDAC patients.Keys: DS-8201a, DUSP6, HER2, KRAS, ulixertinib, pancreatic ductal adenocarcinoma
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models (Section 26) - Mar 9, 2022 - Abstract #AACR2022AACR_5970;
P2
In addition, gene expression analysis showed differential expression of MAPK pathway genes in responders compared to the non-responders.In summary, ulixertinib has exhibited strong pre-clinical activity in a variety of patient-derived xenograft models with atypical BRAF alterations. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, harboring specific BRAF mutations (G469A, L485W, or L597Q) and is currently under clinical evaluation in patients with tumors harboring any atypical BRAF alteration (NCT04488003).
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
BVD-523FB (Ulixertinib) in Patients with Tumors with BRAF Fusions, or with Non-V600E, Non-V600K BRAF Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol EAY131-Z1L (Section 36) - Mar 9, 2022 - Abstract #AACR2022AACR_3958;
Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, harboring specific BRAF mutations (G469A, L485W, or L597Q) and is currently under clinical evaluation in patients with tumors harboring any atypical BRAF alteration (NCT04488003). BVD-523FB (ulixertinib) had no demonstrable evidence of clinical activity in this small, heavily pre-treated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations
- |||||||||| Discovery of CC-91516, a potent and selective ERK/NLK inhibitor, with anti-tumor activity in preclinical cancer models harboring BRAF or CTNNB1 mutation (Section 27) - Mar 9, 2022 - Abstract #AACR2022AACR_3592;
CC-91516 (also called CC0776314), a selective and potent inhibitor of ERK1/2 and NLK, was discovered via a phenotypic screen of a kinase-focused library for compounds that synergize with mTOR kinase inhibitor CC-223 to induce apoptosis in combination with CC-223...Crystal structure of CC-91516 in complex with ERK2 reveals that its 2, 4, 6-trichlorophenyl moiety binds to a unique back pocket of the adenosine-5′-triphosphate (ATP) binding site of ERK2, which is not accessible to other ERK inhibitors such as BVD-523 and GDC-0994...In addition, CC-91516 potently induces apoptosis, inhibits survival, and overcomes resistance to MEK inhibitor trametinib of BRAF or CTNNB1 mutant cancer cells in long-term culture assay in vitro...DMPK and toxicology studies showed robust oral exposure across preclinical species. In summary, CC-91516 has demonstrated preclinical anti-tumor activities and DMPK and safety profiles in support of its clinical development.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Significant efficacy demonstrated with the combination of ulixertinib (ERK1/2 inhibitor) and CDK4/6 inhibitors in MAPK altered models (Section 21) - Mar 9, 2022 - Abstract #AACR2022AACR_3245;
Notably, suppression of protein targets downstream of ERK1/2 were seen with both ulixertinib monotherapy and combination therapy. Similarly, the combination therapy group reduced protein levels involved in cell cycle progression, which was not seen in either monotherapy group alone.The efficacy demonstrated with this preclinical work has proven to be translatable to the clinic as the combination of ulixertinib and palbociclib recently achieved MTD in a Phase I trial in advanced solid tumors including pancreatic cancer (NCT 03454035).
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
The characterization of in vitro models demonstrating a significant delay of acquired resistance to ulixertinib (ERK1/2) (Section 25) - Mar 9, 2022 - Abstract #AACR2022AACR_2684;
Principal component analysis revealed clustering of resistant clones by ulixertinib treatment conditions (concentrations and duration). Differences between parental A375 and ulixertinib resistant clones were revealed, including components of MAPK, HER2, and autophagy markers.This work begins to tease out potential mechanisms of resistance to ulixertinib and guide potential combination partners that could circumvent acquired resistance.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Identification of combination partners to combat acquired resistance to ulixertinib (ERK1/2 inhibitor) using transcriptomics (Section 25) - Mar 9, 2022 - Abstract #AACR2022AACR_2673;
P1
We also validated combinations with autophagy inhibitors, one of which is now being tested in a Phase I clinical trial (NCT04145297).In summary, we have identified some potential resistance mechanisms to ulixertinib and have validated key genes/pathways which may act as synergistic combination targets. This work not only informs future clinical development for ulixertinib but also improves our understanding of the complex interplay between the MAPK and other signaling pathways.
- |||||||||| tamoxifen / Generic mfg.
Journal: Hyperactivation of MAPK Induces Tamoxifen Resistance in SPRED2-Deficient ERα-Positive Breast Cancer. (Pubmed Central) - Feb 26, 2022
Treatment of SPRED2-deficient breast cancer cells with a combination of the ERK 1/2 inhibitor ulixertinib and 4-hydroxytamoxifen (4-OHT) can inhibit cell growth and proliferation and overcome the induced tamoxifen resistance. Taken together, these results indicate that SPRED2 may also be a tumor suppressor for breast cancer and that it is a key regulator of cellular sensitivity to 4-OHT.
- |||||||||| Biomarker, Trial completion date, Trial primary completion date, Metastases: NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) (clinicaltrials.gov) - Feb 18, 2022
P2, N=6452, Recruiting,
Taken together, these results indicate that SPRED2 may also be a tumor suppressor for breast cancer and that it is a key regulator of cellular sensitivity to 4-OHT. Trial completion date: Jun 2022 --> Dec 2025 | Trial primary completion date: Jun 2022 --> Dec 2025
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Biomarker, Trial completion date, Trial primary completion date, Metastases: Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - Jan 19, 2022
P2, N=49, Active, not recruiting,
Clinical Trial Registration: NCT01781429. Trial completion date: Dec 2022 --> Mar 2022 | Trial primary completion date: Dec 2022 --> Mar 2022
- |||||||||| Ibrance (palbociclib) / Pfizer, ulixertinib (BVD-523) / BioMed Valley Discoveries
Enrollment closed, Combination therapy, Metastases: Ulixertinib/Palbociclib in Patients With Advanced Pancreatic and Other Solid Tumors (clinicaltrials.gov) - Jan 10, 2022
P1, N=45, Active, not recruiting,
Trial completion date: Dec 2022 --> Mar 2022 | Trial primary completion date: Dec 2022 --> Mar 2022 Recruiting --> Active, not recruiting
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Biomarker, Trial completion date, Trial primary completion date, Metastases: Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - Jan 6, 2022
P2, N=49, Active, not recruiting,
Recruiting --> Active, not recruiting Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022
- |||||||||| hydroxychloroquine / Generic mfg., tamoxifen / Generic mfg.
Review, Journal: Update on Retinal Drug Toxicities. (Pubmed Central) - Dec 28, 2021
Several newly FDA-approved medications have been associated with acute retinal toxicities, including brolucizumab, MEK inhibitors, ulixertinib, and FGFR inhibitors...Finally, advances in ocular imaging have revealed novel findings in hydroxychloroquine and tamoxifen maculopathies...However, more research is needed to determine the point at which vision loss becomes irreversible. Risks and benefits must be assessed prior to discontinuation of the offending, but potentially lifesaving, therapy.
- |||||||||| Biomarker, Enrollment change, Metastases: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - Dec 20, 2021
P2, N=2316, Recruiting,
Risks and benefits must be assessed prior to discontinuation of the offending, but potentially lifesaving, therapy. N=1500 --> 2316
- |||||||||| S63845 / Servier, Novartis, Ligand, ulixertinib (BVD-523) / BioMed Valley Discoveries
Journal, IO biomarker: Co-targeting MCL-1 and ERK1/2 kinase induces mitochondrial apoptosis in rhabdomyosarcoma cells. (Pubmed Central) - Dec 16, 2021
Overexpression of BCL-2 rescues cell death triggered by Ulixertinib/S63845 co-treatment, confirming that combined inhibition of ERK1/2 and MCL-1 effectively induces cell death of RMS cells via the intrinsic mitochondrial apoptotic pathway. Thus, this study is the first to demonstrate the cytotoxic potency of co-inhibition of ERK1/2 and MCL-1 for RMS treatment.
- |||||||||| Nexavar (sorafenib) / Bayer, Amgen
Clinical, FDA event, Review, Journal: Mini review: The FDA-approved prescription drugs that target the MAPK signaling pathway in women with breast cancer. (Pubmed Central) - Oct 31, 2021
The most common breast cancer drugs that regulate or inhibit the MAPK pathway may include Farnesyltransferase inhibitors (FTIs), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, and Teriflunomide. In this review, we will discuss the roles of the MAPK/RAS/RAF/MEK/ERK pathway in BC and summarize the FDA-approved prescription drugs that target the MAPK signaling pathway in women with BC.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Journal: Inhibition of the ERK/RSK kinase cascade limits Chlamydia trachomatis infection. (Pubmed Central) - Oct 9, 2021
Moreover, BVD-523, a first-in-class ERK1/2 inhibitor currently undergoing a phase II clinical trial, suppressed Chlamydia infection both in cell culture and in a mouse model. These observations demonstrated not only that the ERK/RSK pathway plays a critical role in Chlamydia infection, but also that these kinases have potential as targets for host-directed therapy against Chlamydia trachomatis.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Journal, Epigenetic controller: In Silico Screening Reveals Histone Deacetylase 7 and ERK1/2 as Potential Targets for Artemisinin Dimer and Artemisinin Dimer Hemisuccinate. (Pubmed Central) - Sep 19, 2021
These observations demonstrated not only that the ERK/RSK pathway plays a critical role in Chlamydia infection, but also that these kinases have potential as targets for host-directed therapy against Chlamydia trachomatis. This findings suggest that artemisinin dimer and artemisinin dimer hemisuccinate could be promising anticancer drug agents, with better therapeutic efficacy than ulixertinib and apicidin in the treatment of cancer via inhibition of HDAC7, ERK1 and ERK2.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries
Biomarker, Trial completion date, Trial primary completion date, Metastases: Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - Sep 13, 2021
P2, N=49, Active, not recruiting,
This findings suggest that artemisinin dimer and artemisinin dimer hemisuccinate could be promising anticancer drug agents, with better therapeutic efficacy than ulixertinib and apicidin in the treatment of cancer via inhibition of HDAC7, ERK1 and ERK2. Trial completion date: Dec 2025 --> Dec 2021 | Trial primary completion date: Dec 2025 --> Dec 2021
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