Study SL-801-0115 is a dose-escalation study evaluating multiple doses and schedules of orally administered SL-801 in patients with Advanced Solid Tumors

Start Date23 Feb 2016

Sponsor / Collaborator

Stemline Therapeutics, Inc.

100 Clinical Results associated with Felezonexor

100 Translational Medicine associated with Felezonexor

100 Patents (Medical) associated with Felezonexor

Literatures (Medical) associated with Felezonexor

01 Dec 2014·Journal of Hematology & OncologyQ1 · MEDICINE

Nucleo-cytoplasmic transport as a therapeutic target of cancer

Q1 · MEDICINE

ReviewOA

Author: Sharon Shacham ; Giovanni Luca Gravina ; Claudio Festuccia ; William Senapedis ; Erkan Baloglu ; Dilara McCauley

Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer.

01 Dec 2014·Molecular Cancer TherapeuticsQ2 · MEDICINE

CBS9106-Induced CRM1 Degradation Is Mediated by Cullin Ring Ligase Activity and the Neddylation Pathway

Q2 · MEDICINE

Article

Author: Kawabe, Takumi ; Saito, Naoya ; Sakakibara, Keiichi ; VonHoff, Daniel D. ; Sato, Takuji ; Friedman, Jonathan M. ; Kufe, Donald W.

AbstractChromosome region maintenance 1 (CRM1) mediates the nuclear export of proteins and mRNAs, and is overexpressed in various cancers. Recent studies have also reported that CRM1 protein expression is a negative prognostic factor in patients with cancer. Therefore, CRM1 is considered a potential target for anticancer therapy. Our previous study demonstrated that CBS9106, a synthetic small-molecular inhibitor of CRM1, decreases CRM1 protein through proteasomal degradation without affecting CRM1 mRNA levels. However, the mechanism by which CRM1 is degraded is not well understood. Here, we demonstrate a novel signaling pathway that plays an important role in CBS9106-induced CRM1 degradation. We found that MLN4924, a selective inhibitor of NEDD8-activating enzyme (NAE), effectively inhibits cullin neddylation and attenuates CBS9106-induced CRM1 degradation in a time- and dose-dependent manner. MLN4924 also attenuated CBS9106-induced nuclear accumulation of Ran-binding protein 1 (RanBP1), cell growth inhibition, and apoptosis. Furthermore, RNAi-mediated knockdown of neddylation pathway proteins (NEDD8 and UBA3) or cullin ring ligase (CRL) component protein (Rbx1) attenuated CRM1 protein degradation and G1 phase cell-cycle arrest by CBS9106. Knockdown of CSN5 or CAND1 also partially inhibited CBS9106-induced CRM1 degradation. These findings demonstrate that CBS9106-induced CRM1 degradation is conferred by CRL activity involving the neddylation pathway, and that this response to CBS9106 leads to cell growth inhibition and apoptosis. Mol Cancer Ther; 13(12); 3013–23. ©2014 AACR.

01 Apr 2012·Biochemical PharmacologyQ2 · MEDICINE

Nuclear export of proteins and drug resistance in cancer

Q2 · MEDICINE

Review

Author: Daniel M. Sullivan ; Joel G. Turner ; Jana Dawson

The intracellular location of a protein is crucial to its normal functioning in a cell. Cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of a cell to effectively evade anti-neoplastic mechanisms. CRM1-mediated export is increased in various cancers. Proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, APC, p53, BRAC1, FOXO proteins, INI1/hSNF5, galectin-3, Bok, nucleophosmin, RASSF2, Merlin, p21(CIP), p27(KIP1), N-WASP/FAK, estradiol receptor and Tob, drug targets topoisomerase I and IIα and BCR-ABL, and the molecular chaperone protein Hsp90. Here, we review in detail the current processes and known structures involved in the export of a protein through the nuclear pore complex. We also discuss the export receptor molecule CRM1 and its binding to the leucine-rich nuclear export signal of the cargo protein and the formation of a nuclear export trimer with RanGTP. The therapeutic potential of various CRM1 inhibitors will be addressed, including leptomycin B, ratjadone, KOS-2464, and specific small molecule inhibitors of CRM1, N-azolylacrylate analogs, FOXO export inhibitors, valtrate, acetoxychavicol acetate, CBS9106, and SINE inhibitors. We will also discuss examples of how drug resistance may be reversed by targeting the exported proteins topoisomerase IIα, BCR-ABL, and galectin-3. As effective and less toxic CRM1 export inhibitors become available, they may be used as both single agents and in combination with current chemotherapeutic drugs. We believe that the future development of low-toxicity, small-molecule CRM1 inhibitors may provide a new approach to treating cancer.

100 Deals associated with Felezonexor

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	US	Stemline Therapeutics, Inc.	23 Feb 2016
Solid tumor	Phase 1	IT	Menarini Von Heyden GmbH	30 Jan 2022

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02667873 (ESMO2020) Manual	Phase 1	Relapsed Solid Neoplasm	-	Felezonexor	(jmspujpydy) = nausea (73%), vomiting (62%), fatigue (51%), decreased appetite (33%), and diarrhea (27%) mbrncvttry (zbspeqsndq ) View more	Positive	17 Sep 2020
NCT02667873 (ESMO2018) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	35	Felezonexor	(xjivlmannt) = Not reached atsnldvgrk (fyublnsalv ) View more	Positive	22 Oct 2018

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