Xpovio (selinexor)

Key findings highlight the effectiveness of selinexor in preclinical studies, particularly against KRAS-mutant NSCLC and in combination with chemotherapy for SCLC. The review concludes with a discussion of future directions and underscores the potential of selinexor to improve the treatment strategies for lung cancer.

P1, N=78, Completed, Sanjay Mohan | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Sep 2024

P3, N=222, Recruiting, Stichting European Myeloma Network | Active, not recruiting --> Recruiting | N=109 --> 222

The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions...Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.

P2, N=82, Not yet recruiting, Ruijin Hospital

Selinexor/KPT-185 is an allosteric degrader. We have explained how drug-induced protein degradation is mediated by a CRL5 system through an allosteric rather than a molecular glue mechanism, expanding the modes of targeted protein degradation beyond the well-known molecular glues of CRL4.

P3, N=109, Active, not recruiting, Stichting European Myeloma Network | Recruiting --> Active, not recruiting | N=222 --> 109

P1, N=39, Recruiting, Mayo Clinic | Trial completion date: Dec 2025 --> Aug 2027

P2, N=52, Active, not recruiting, Academic and Community Cancer Research United | Recruiting --> Active, not recruiting

P3, N=126, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P1, N=221, Terminated, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Sep 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Sep 2024; Administratively Complete

P4, N=42, Not yet recruiting, Meishan City Peoples Hospital; Meishan City Peoples Hospital

P2, N=40, Recruiting, The First Affiliated Hospital with Nanjing Medical University; The First Affiliated Hospital with Nanjing

P1/2, N=300, Recruiting, Karyopharm Therapeutics Inc | Active, not recruiting --> Recruiting

Meanwhile, the latest clinical trials have confirmed that whether it is a single agent or combined with other chemotherapy regimens, selinexor can also achieve good therapeutic effects in patients with leukemia and lymphoma. This review summarizes the results of preclinical studies and clinical trials of selinexor in treatment of non-MM hematological malignancies, aiming to explore how to choose single agent or in combination with other regimens as induction chemotherapy.

P2, N=28, Not yet recruiting, Ruijin Hospital

P2, N=18, Not yet recruiting, Ruijin Hospital

P2, N=15, Terminated, Karyopharm Therapeutics Inc | N=40 --> 15 | Trial completion date: Jan 2024 --> Sep 2023 | Active, not recruiting --> Terminated; The trial was terminated due to a lack of sufficient anti-melanoma tumor signal for the combination of selinexor + pembrolizumab.

P3, N=402, Completed, Karyopharm Therapeutics Inc | Active, not recruiting --> Completed

P1/2, N=38, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

P1/2, N=37, Recruiting, Samsung Medical Center

P2, N=18, Active, not recruiting, University of Colorado, Denver | Recruiting --> Active, not recruiting

P=N/A, N=120, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression.

These findings suggest that selinexor inhibits the progression of cholangiocarcinoma by targeting XPO1 and promoting the nuclear accumulation of PEG3 protein, thereby hindering the cell cycle and inducing apoptosis.

In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies.

This review summarizes current data on treatment with SINE, TCR therapy, and CELMoDs and explores their mechanism of resistance. Understanding these resistance mechanisms is critical for developing strategies to overcome treatment failure and improve therapeutic outcomes.

P2, N=42, Recruiting, Sun Yat-sen University

P=N/A, N=100, Recruiting, iOMEDICO AG | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Sep 2025 --> Sep 2026

P1/2, N=97, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

Many structurally diverse electrophilic small molecules target exportin-1 (XPO1/CRM1) at cysteine 528, including the selective inhibitor of nuclear export (SINE) selinexor, which was FDA-approved as an anticancer agent in 2019...We observe that the electrophilic moiety of Cys528-targeting small molecules plays a decisive role in the cellular behavior observed, with subtle changes in electrophile structure being sufficient to convert XPO1-targeting probes to different pharmacological classes. This investigation represents a unique case study in which the electrophile functionality used to target a specific cysteine determines the pharmacological effect among diverse XPO1-targeting small molecules.

Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. These targets were tested in vivo using Sf3b1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS.

We conclude that XPO1 and DDX19A/B coordinately regulate cellular MCL1 levels and propose that DDX19A/B could serve as biomarkers for selinexor treatment. Moreover, pharmacological targeting of DDX19 paralogs may represent a potential strategy to induce intrinsic apoptosis in leukemia cells.

P2; Recruiting --> Withdrawn | N=35 --> 0

Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL.

Analyses of PDB holdings, the scientific literature, and related documents for each drug-target combination revealed that the impact of structural biologists and public-domain 3D biostructure data was broad and substantial, ranging from understanding target biology (100% of all drug targets), to identifying a given target as likely druggable (100% of all targets), to structure-guided drug discovery (>80% of all new small-molecule drugs, made up of 50% confirmed and >30% probable cases). In addition to aggregate impact assessments, illustrative case studies are presented for six first-in-class small-molecule anti-cancer drugs, including a selective inhibitor of nuclear export targeting Exportin 1 (selinexor, Xpovio), an ATP-competitive CSF-1R receptor tyrosine kinase inhibitor (pexidartinib,Turalia), a non-ATP-competitive inhibitor of the BCR-Abl fusion protein targeting the myristoyl binding pocket within the kinase catalytic domain of Abl (asciminib, Scemblix), a covalently-acting G12C KRAS inhibitor (sotorasib, Lumakras or Lumykras), an EZH2 methyltransferase inhibitor (tazemostat, Tazverik), and an agent targeting the basic-Helix-Loop-Helix transcription factor HIF-2α (belzutifan, Welireg).

P1/2, N=56, Active, not recruiting, Antengene Corporation | Terminated --> Active, not recruiting | Trial completion date: May 2024 --> Dec 2024 | Trial primary completion date: May 2024 --> Dec 2024

P1/2, N=41, Terminated, University of Texas Southwestern Medical Center | Completed --> Terminated; Funding Sponsor no longer supporting study

P1, N=16, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2024 --> Dec 2024

P=N/A, N=20, Not yet recruiting, Durham VA Medical Center

In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931).

P2, N=118, Recruiting, Karyopharm Therapeutics Inc | Not yet recruiting --> Recruiting