Search

WO-2026093905-A1 - NEW SELECTIVE ERAP INHIBITOR CANTHIN-6-ONE AND USES THEREOF

WO2026093905A1WO 2026093905 A1WO2026093905 A1WO 2026093905A1WO-2026093905-A1

Abstract

The present invention relates to canthin-6-one and compositions comprising it for the treatment and/or prevention of relapses of Hedgehog-dependent tumors (HH) tumors, or diseases characterized by aberrant expression of endoplasmic reticulum aminopeptidases (ERAP), the use of canthin-6-one as an ERAP inhibitor or marker for the detection of ERAP, and said therapeutic treatments comprising the administration of canthin-6-one in a therapeutically effective dosage to a patient in need thereof.

Inventors

  • DI MARCOTULLIO, Lucia
  • FRUCI, DORIANA
  • MORI, Mattia
  • BOTTA, BRUNO
  • BUFALIERI, Francesca
  • GHIRGA, Francesca
  • QUAGLIO, Deborah
  • Cucinotta, Antonino
  • INFANTE, Paola
  • LOSPINOSO SEVERINI, Ludovica
  • CAMMARONE, Silvia

Assignees

  • UNIVERSITA' DEGLI STUDI DI ROMA "LA SAPIENZA"
  • OSPEDALE PEDIATRICO BAMBINO GESÙ IRCCS
  • UNIVERSITÀ DEGLI STUDI DI SIENA

Dates

Publication Date
20260507
Application Date
20251028
Priority Date
20241104

Claims (10)

  1. 1. Canthin-6-one or a pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use in the treatment of Hedgehog (HH) dependent tumours or in the treatment and/or prevention of relapses of said tumours
  2. 2. Canthin-6-one or the pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use according to claim 1 wherein said tumours are Sonic Hedgehog (SHH) dependent tumours.
  3. 3. Canthin-6-one or the pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use according to any one of claims 1 to 2 wherein said tumours are selected within: Sonic Hedgehog subgroup medulloblastoma (SHH-MB), basal cell carcinoma, rhabdomyosarcoma, preferably wherein said tumour is SHH-MB.
  4. 4. Canthin-6-one or the pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use in the treatment of conditions that exhibit aberrant positive expression of endoplasmic reticulum aminopeptidase (ERAP), wherein said aberrant positive expression is a constitutive expression of the ERAP protein in a tissue wherein it is normally absent, or an overexpression of ERAP compared to the expression thereof in a corresponding healthy control tissue, preferably wherein said protein ERAP is ERAP1 and/or ERAP2
  5. 5. Canthin-6-one or the pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use according to claim 4 wherein the administration of said molecule causes a therapeutic effect through the inhibition of ERAP.
  6. 6. Canthin-6-one or the pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use according to any one of claims 4 or 5 wherein the treatment comprises a step for determining whether a patient presents an aberrant positive expression of ERAP and one or more administration steps of said Canthin-6-one to patients that present said aberrant positive expression of ERAP.
  7. 7. The pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use according to any one of claims from 1 to 6, in liquid, solid, or semi-solid form.
  8. 8. The pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use according to any one of claims from 1 to 7 in the form of a composition for topical, enteral, oral, sublingual, nasal, oro- nasopharyngeal, systemic, intravenous, intraperitoneal, intrathecal, intramuscular, subcutaneous, intratumoral, or inhalation administration, preferably in the form of a tablet, solution, suspension, emulsion, syrup, soft or hard capsule, aerosol, injectable solution, injectable suspension, injectable emulsion, gel, ointment, cream, lotion, or spray
  9. 9. Canthin-6-one or the pharmaceutical composition comprising Canthin-6-one and at least one pharmaceutically acceptable vehicle for use according to any one of claims from 4 to 6 wherein said condition is an autoimmune and/or autoinflammatory disease, hypertension, a viral infection, or cancer, preferably wherein said autoimmune and/or autoinflammatory diseases are ankylosing spondylitis, Behget's disease, psoriasis, or Birdshot chorioretinopathy and preferably wherein said cancer is melanoma, leukemia, lymphoma, breast cancer, colon cancer, thyroid cancer, lung cancer, cervical cancer, prostate cancer, kidney cancer, bladder cancer.
  10. 10. In vitro or ex vivo use of cathin-6-one as an inhibitor of ERAP.

Description

NEW SELECTIVE ERAP INHIBITOR CANTHIN-6-ONE AND USES THEREOF The present invention relates to canthin-6-one and compositions comprising it for the treatment and/or prevention of relapses of Hedgehog-dependent tumors (HH) tumors, or diseases characterized by aberrant expression of endoplasmic reticulum aminopeptidases (ERAP), the use of canthin-6-one as an ERAP inhibitor or marker for the detection of ERAP, and said therapeutic treatments comprising the administration of canthin-6-one in a therapeutically effective dosage to a patient in need thereof. BACKGROUND The Hedgehog (HH) signaling pathway plays a crucial role in embryogenesis, tissue development, and stem cell maintenance. Its aberrant activation, induced by alterations in the transcriptional activity of specific HH factors (such as Ptch, Smo, Sufu, Gli1 , and Gli2), promotes tumorigenesis mechanisms in various tumors, including basal cell carcinoma (BCC) and medulloblastoma (MB). Medulloblastoma (MB) is the most common malignant brain tumor in children. It is divided into four molecular subgroups: Wingless (WNT), Sonic-Hedgehog (SHH), Group 3 (G3), and Group 4 (G4). In the pathogenesis of the SHH subgroup, the SHH signaling pathway plays a key role. Conventional therapeutic approaches, such as surgery, radiation, and chemotherapy, often cause significant adverse effects. A thorough understanding of the molecular mechanisms underlying the development and progression of MB-SHH has led to the identification of new therapeutic strategies for the treatment of this tumor. To date, significant progress has been made in the development of SHH pathway inhibitors, especially for drugs that target the SMO activator receptor. Although three of these have entered clinical trials for the treatment of SHH-dependent tumors, the adverse side effects resulting from their administration and the emergence of drug resistance, mainly due to mutations in the SMO receptor, have greatly limited the safety and efficacy of these drugs. A further obstacle to the use of these inhibitors is the existence of SMO-independent Hedgehog pathway activation mechanisms, which highlight the need to identify new components of the pathway to use as alternative drug targets. In this context, endoplasmic reticulum aminopeptidase 1 (ERAP1 in humans, ERAAP in mice; Saveanu L et al, Nat Immunol 2005; UniProt codes Q9NZ08 and Q9EQH2) has emerged as a valid drug target for combating HH-dependent tumors. This enzyme has recently been described as a new activator of the SHH pathway, promoting the stabilization of GLI transcription factors, the final effectors of the pathway. Specifically, it has been discovered that ERAP1 interacts with the deubiquitinase USP47 to promote the degradation of pTrCP, an F-box protein of the Skp1-Cul1-Fbox (SCF) E3 ligase complex normally stabilized by LISP47. Since the SCFpTrCP complex is responsible for regulating GLI activator proteins, the latter are no longer degraded and are able to promote the expression of SHH pathway target genes, promoting cell proliferation and tumorigenesis. In accordance with this molecular mechanism, it has been widely demonstrated that both genetic and pharmacological inhibition of ERAP1 are able to suppress SHH-MB growth in vitro and in vivo. It is also known that abnormalities in ERAP1 expression have been linked to autoimmune diseases such as ankylosing spondylitis and psoriasis. It is reported in the literature that inhibition of ERAP1 may help modulate the immune response and reduce inflammation in these diseases. More generally, inhibitors of the enzymes ERAP 1 and 2 (endoplasmic reticulum aminopeptidases) are primarily being studied for their potential in the treatment of various autoimmune diseases and cancer, as they are involved in the processing of peptides for presentation by class I molecules of the major histocompatibility complex (MHC), which is crucial for the immune response. By inhibiting ERAP 1 and/or 2 enzymes, immune responses can be modulated, potentially reducing inflammation in autoimmune conditions or enhancing antitumor immunity in cancer therapy. It is therefore of great interest to identify new ERAP inhibitors for use in the treatment of diseases wherein there is altered activity and/or expression of these enzymes, including HH-dependent tumors. SUMMARY OF THE INVENTION The authors of this invention have surprisingly discovered that Canthin-6-one (IUPAC name 1 ,6-diazatetracicloesadeca-3,5(16),6,8,10,12, 14-eptaen-2-one), an indole alkaloid already known in the literature for its anti-mycobacterial properties, is an effective inhibitor of ERAP. Surprisingly, the authors found and demonstrated that Canthin-6-one exhibits inhibitory activity on ERAP. This inhibitory activity, being exerted both on the enzymatic activity of ERAP and on its binding affinity to other proteins (Figures 1 and 3), interferes with the ability of ERAP to form complexes with other proteins, resulting in the inhibition of the functions