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    DRUG CLASS:

    Sortilin inhibitor

    Related drugs:
    3ms
    An anti-sortilin affibody-peptide fusion inhibits sortilin-mediated progranulin degradation. (PubMed, Front Immunol)
    Our results introduce A3-PGRNC15* as a promising new agent with therapeutic potential for the treatment of frontotemporal dementia. Furthermore, the work highlights means to increase binding affinity through synergistic contribution from two orthogonal polypeptide units.
    Journal
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    SORT1 (Sortilin 1) • GRN (Granulin Precursor)
    8ms
    Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing. (PubMed, Front Immunol)
    A weekly administration of TH1902 as a single agent in a murine B16-F10 melanoma syngeneic tumor model demonstrated superior tumor growth inhibition than did docetaxel. TH1902 inhibited cell proliferation and triggered apoptosis and senescence in B16-F10 cells in vitro, while inducing several downstream effectors of the cGAS/STING pathway and the expression of MHC-I and PD-L1. This is the first evidence that TH1902 exerts its antitumor activity, in part, through modulation of the immune tumor microenvironment and that the combination of TH1902 with checkpoint inhibitors (anti-PD-L1) could lead to improved clinical outcomes.
    Journal • PD(L)-1 Biomarker • IO biomarker • Tumor cell
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    SORT1 (Sortilin 1) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CASP3 (Caspase 3) • GZMB (Granzyme B)
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    docetaxel • sudocetaxel zendusortide (TH 1902)
    9ms
    PROGRESS-AD: Efficacy and Safety of GSK4527226 [AL101] in Participants With Early Alzheimer's Disease (clinicaltrials.gov)
    P2, N=282, Recruiting, GlaxoSmithKline | Not yet recruiting --> Recruiting
    Enrollment open
    11ms
    Continuation Study for Latozinemab (clinicaltrials.gov)
    P3, N=35, Enrolling by invitation, Alector Inc. | Recruiting --> Enrolling by invitation
    Enrollment status
    1year
    A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3) (clinicaltrials.gov)
    P3, N=110, Active, not recruiting, Alector Inc. | Recruiting --> Active, not recruiting | N=180 --> 110 | Trial completion date: Dec 2023 --> Oct 2027 | Trial primary completion date: Oct 2023 --> Sep 2025
    Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date
    |
    NEFL (Neurofilament Light Chain)
    1year
    Continuation Study for Latozinemab (clinicaltrials.gov)
    P3, N=35, Recruiting, Alector Inc.
    New P3 trial
    1year
    PROGRESS-AD: Efficacy and Safety of GSK4527226 [AL101] in Participants With Early Alzheimer's Disease (clinicaltrials.gov)
    P2, N=282, Not yet recruiting, GlaxoSmithKline
    New P2 trial
    1year
    TH1902 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=70, Recruiting, Theratechnologies | Active, not recruiting --> Recruiting
    Enrollment open • Metastases
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    CD4 (CD4 Molecule)
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    SORT1 expression
    |
    sudocetaxel zendusortide (TH 1902)
    1year
    TH1902 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=70, Active, not recruiting, Theratechnologies | Trial completion date: Mar 2023 --> Dec 2024 | Trial primary completion date: Mar 2023 --> Dec 2024
    Trial completion date • Trial primary completion date • Metastases
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    CD4 (CD4 Molecule)
    |
    SORT1 expression
    |
    sudocetaxel zendusortide (TH 1902)
    over1year
    Sudocetaxel zendusortide (TH1902), a novel sortilin-receptor (SORT1)-targeting peptide-drug-conjugate (PDC) in patients (pts) with advanced solid tumors: Results from part 1 (dose-escalation) of a phase 1, open-label study. (ASCO 2023)
    TH1902 is a first-in-class PDC targeting SORT1, that consists of 2 molecules of docetaxel attached to the TH19P01 peptide via a cleavable succinyl linker. Although biological activity has been observed, the optimal dosing regimen of TH1902 is currently under evaluation. Clinical trial information: NCT04706962.
    Clinical • P1 data • Metastases
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    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • SORT1 (Sortilin 1)
    |
    SORT1 expression
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    docetaxel • sudocetaxel zendusortide (TH 1902)
    over1year
    The peptide-drug conjugate sudocetaxel zendusortide (TH1902) potentiates anti-tumoral activity of the anti-PD-L1 checkpoint inhibitor and induces immune cell infiltration in a B16-F10 syngeneic melanoma model (AACR 2023)
    Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate (PDC) of the sortilin (SORT1)-binding peptide TH19P01 ester-linked to two docetaxel moieties, has been shown to exert superior anti-cancer activities in multiple cancer models including melanoma syngeneic and xenograft murine models. This is the first demonstration that immune cell infiltration patterns play a pivotal role in the TH1902-associated anti-tumoral response. Combination of TH1902 with checkpoint inhibitors (anti-PD-L1) further reveals that this may lead to improved clinical outcomes in future immunotherapy translational approaches.
    Checkpoint inhibition • Immune cell
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    SORT1 (Sortilin 1) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CASP3 (Caspase 3) • GZMB (Granzyme B)
    |
    docetaxel • sudocetaxel zendusortide (TH 1902)
    almost2years
    TH1902 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=70, Active, not recruiting, Theratechnologies | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    CD4 (CD4 Molecule)
    |
    SORT1 expression
    |
    sudocetaxel zendusortide (TH 1902)
    almost2years
    Case Study: A First-In-Class Peptide Drug Conjugate (PDC) Platform Targeting Sortilin (SORT1) Receptor Positive Cancers (ADC London 2023)
    Synopsis Understanding why the normal function of a scavenger receptor, SORT1, can be exploited to rapidly transport novel peptide drug conjugates (PDCs) into cancer cells Discussing the over expression of SORT1 in many solid tumours Learn about Thera’s lead PDC candidate, TH1902, across multiple solid tumours Review the potential of this novel SORT1+ platform for future developments
    Clinical
    |
    SORT1 (Sortilin 1)
    |
    SORT1 expression
    |
    sudocetaxel zendusortide (TH 1902)
    2years
    The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells. (PubMed, Pharmaceutics)
    These events were unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. Therapeutic efficacy was further observed when carboplatin was combined to TH1902. Overall, TH1902 exerts a superior anticancer activity than the unconjugated docetaxel, in part, by circumventing the CSC drug resistance phenotype that could potentially reduce cancer recurrence attributable to CSC.
    Journal
    |
    ABCB1 (ATP Binding Cassette Subfamily B Member 1) • SORT1 (Sortilin 1) • SOX2 • NANOG (Nanog Homeobox)
    |
    SORT1 expression
    |
    carboplatin • docetaxel • sudocetaxel zendusortide (TH 1902) • cyclosporin A microemulsion
    over2years
    The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers. (PubMed, Cancers (Basel))
    Furthermore, TH1902 combination with carboplatin also demonstrated better efficacy when compared to both taxanes-carboplatin combinations. Overall, TH1902 shows better in vivo efficacy, compared to that of docetaxel and even paclitaxel, against SORT1-positive ovarian and endometrial cancers and could be safely combined with carboplatin.
    Journal
    |
    SORT1 (Sortilin 1)
    |
    SORT1 expression
    |
    carboplatin • paclitaxel • docetaxel • sudocetaxel zendusortide (TH 1902)
    over2years
    TH1902 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=70, Recruiting, Theratechnologies | Trial completion date: Mar 2022 --> Mar 2023 | Trial primary completion date: Mar 2022 --> Mar 2023
    Trial completion date • Trial primary completion date
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    CD4 (CD4 Molecule)
    |
    SORT1 expression
    |
    sudocetaxel zendusortide (TH 1902)
    over2years
    The peptide-drug conjugate TH1902 inhibits growth of subcutaneous melanoma xenografts and formation of lung metastases in a syngeneic mouse model (AACR 2022)
    Moreover, considerable weight loss was associated with docetaxel treatment over 24 days while TH1902 treatments resulted in no net change in mouse body weights. In this syngeneic model, TH1902 is more tolerated and effective than docetaxel at inhibiting both melanoma xenograft growth and metastatic formation.
    Preclinical
    |
    SORT1 (Sortilin 1)
    |
    SORT1 expression
    |
    docetaxel • sudocetaxel zendusortide (TH 1902)
    over2years
    Anti-cancer efficacy of TH1902, a SORT1 docetaxel peptide-drug conjugate, against ovarian and endometrial cancers xenografts alone or in combination with carboplatin (AACR 2022)
    Mice bearing A-2780 xenograft tumors were treated with TH1902, paclitaxel or docetaxel alone, as well as with each in combination with carboplatin. Moreover, TH1902 combined with carboplatin also demonstrated better efficacy than did either of the taxane-carboplatin combinations. Overall, the results indicate that TH1902 possesses an in vivo efficacy superior to those of docetaxel against ovarian and endometrial cancers in the animal models tested, and that TH1902 could be safely combined with carboplatin to reach optimal inhibition of tumor growth.
    Clinical • Combination therapy
    |
    SORT1 (Sortilin 1)
    |
    carboplatin • paclitaxel • docetaxel • sudocetaxel zendusortide (TH 1902)
    3years
    New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells. (PubMed, Front Oncol)
    In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.
    Journal
    |
    SORT1 (Sortilin 1) • CD31 (Platelet and endothelial cell adhesion molecule 1) • MMP9 (Matrix metallopeptidase 9)
    |
    doxorubicin hydrochloride • pegylated liposomal doxorubicin • sudocetaxel zendusortide (TH 1902) • TH-1904
    3years
    TH1902, a new docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer. (PubMed, Cancer Sci)
    Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • BCL2L1 (BCL2-like 1) • SORT1 (Sortilin 1)
    |
    SORT1 positive
    |
    docetaxel • sudocetaxel zendusortide (TH 1902)
    over3years
    [VIRTUAL] Granulin peptides induce breast cancer stem cell propagation via sortilin (EACR 2021)
    We recently published that secretion of progranulin was increased by hypoxia in ERα positive breast cancer cell cultures, which induce BCSC propagation, demonstrated by an increase in mammosphere formation in vitro , as well as metastasis formation in mice. We also observed that the cleaved peptide domain granulin A induce similar cancer stem cell spreading.Conclusion These results suggests that progranulin peptides induce expansion of BCSCs via sortilin, similar to progranulin, emphasising the receptor sortilin as an important therapeutic target, not only to inhibit the progranulin-sortilin communication axis but also cleaved peptides of progranulin.
    SORT1 (Sortilin 1)
    |
    ER positive
    over3years
    [VIRTUAL] Granulin peptides induce breast cancer stem cell propagation via sortilin (EACR 2021)
    We recently published that secretion of progranulin was increased by hypoxia in ERα positive breast cancer cell cultures, which induce BCSC propagation, demonstrated by an increase in mammosphere formation in vitro , as well as metastasis formation in mice. We also observed that the cleaved peptide domain granulin A induce similar cancer stem cell spreading.Conclusion These results suggests that progranulin peptides induce expansion of BCSCs via sortilin, similar to progranulin, emphasising the receptor sortilin as an important therapeutic target, not only to inhibit the progranulin-sortilin communication axis but also cleaved peptides of progranulin.
    SORT1 (Sortilin 1)
    |
    ER positive
    over3years
    [VIRTUAL] Granulin peptides induce breast cancer stem cell propagation via sortilin (EACR 2021)
    We recently published that secretion of progranulin was increased by hypoxia in ERα positive breast cancer cell cultures, which induce BCSC propagation, demonstrated by an increase in mammosphere formation in vitro , as well as metastasis formation in mice. We also observed that the cleaved peptide domain granulin A induce similar cancer stem cell spreading.Conclusion These results suggests that progranulin peptides induce expansion of BCSCs via sortilin, similar to progranulin, emphasising the receptor sortilin as an important therapeutic target, not only to inhibit the progranulin-sortilin communication axis but also cleaved peptides of progranulin.
    SORT1 (Sortilin 1)
    |
    ER positive
    over3years
    [VIRTUAL] Granulin peptides induce breast cancer stem cell propagation via sortilin (EACR 2021)
    We recently published that secretion of progranulin was increased by hypoxia in ERα positive breast cancer cell cultures, which induce BCSC propagation, demonstrated by an increase in mammosphere formation in vitro , as well as metastasis formation in mice. We also observed that the cleaved peptide domain granulin A induce similar cancer stem cell spreading.Conclusion These results suggests that progranulin peptides induce expansion of BCSCs via sortilin, similar to progranulin, emphasising the receptor sortilin as an important therapeutic target, not only to inhibit the progranulin-sortilin communication axis but also cleaved peptides of progranulin.
    SORT1 (Sortilin 1)
    |
    ER positive
    over3years
    TH1902 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=65, Recruiting, Theratechnologies | Not yet recruiting --> Recruiting
    Clinical • Enrollment open
    |
    CD4 (CD4 Molecule)
    |
    sudocetaxel zendusortide (TH 1902)
    over3years
    [VIRTUAL] TH1902, a docetaxel peptide-drug conjugate, shows pre-clinical efficacy in several Sortilin-positive (SORT1+) cancers (AACR 2021)
    In all cases, TH1902 showed more potent inhibition than Docetaxel. These results strongly support future clinical development of TH1902 as novel therapeutics in SORT1+ cancers.
    Preclinical
    |
    SORT1 (Sortilin 1)
    |
    SORT1 expression • SORT1 positive
    |
    docetaxel • sudocetaxel zendusortide (TH 1902)
    4years
    The membrane protein sortilin can be targeted to inhibit pancreatic cancer cell invasion. (PubMed, Am J Pathol)
    Sortilin inhibition also decreased the phosphorylation of the focal adhesion kinase (FAK) in Tyr925. Together, these data reveal that sortilin contributes to pancreatic cancer invasion and could eventually be targeted in therapy.
    Journal
    |
    SORT1 (Sortilin 1)
    4years
    Precision medicine for human cancers with Notch signaling dysregulation (Review). (PubMed, Int J Mol Med)
    Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat and others) and antibody‑based biologics targeting Notch ligands or receptors [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) and others] have been developed as investigational drugs...Phase III clinical trials of Rova‑T for patients with small‑cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch‑related knowledge‑base and optimize Notch‑targeted therapy for patients with cancer.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • FLT3 (Fms-related tyrosine kinase 3) • MET (MET proto-oncogene, receptor tyrosine kinase) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR3 (Fibroblast growth factor receptor 3) • NOTCH1 (Notch 1) • FGFR (Fibroblast Growth Factor Receptor) • CD19 (CD19 Molecule) • TNFRSF8 (TNF Receptor Superfamily Member 8) • CCND1 (Cyclin D1) • CD79B (CD79b Molecule) • HGF (Hepatocyte growth factor) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • TNFA (Tumor Necrosis Factor-Alpha) • TNFRSF17 (TNF Receptor Superfamily Member 17) • NOTCH2 (Notch 2) • DLL3 (Delta Like Canonical Notch Ligand 3) • CD44 (CD44 Molecule) • NOTCH3 (Notch Receptor 3) • NOTCH4 (Notch 4) • RAC1 (Rac Family Small GTPase 1) • BMI1 (BMI1 proto-oncogene, polycomb ring finger) • FGF (Fibroblast Growth Factor) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
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    NOTCH1 mutation
    |
    Rova-T (rovalpituzumab tesirine) • Ogsiveo (nirogacestat) • AL101 • AMG 119 • dilpacimab (ABT-165)
    over4years
    Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3β/β-catenin/twist pathway. (PubMed, Cell Death Dis)
    Taken together, our results demonstrate a critical role of sortilin in glioblastoma invasion and EMT-like mesenchymal transition, indicating that sortilin contributes to glioblastoma progression. These data also highlight the dramatic antitumor effects of AF38469 in glioblastoma, suggesting that AF38469 is a potentially powerful antitumor agent for sortilin-overexpressing human glioblastoma.
    Journal
    |
    CTNNB1 (Catenin (cadherin-associated protein), beta 1) • SORT1 (Sortilin 1) • GSK3B (Glycogen Synthase Kinase 3 Beta)