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    DRUG CLASS:

    Notch-4 receptor inhibitor

    Related drugs:
    18d
    AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov)
    P1, N=14, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    AL101
    6ms
    AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov)
    P1, N=14, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025
    Trial completion date • Trial primary completion date
    |
    AL101
    9ms
    TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov)
    P2, N=18, Terminated, Ayala Pharmaceuticals, Inc, | N=67 --> 18 | Active, not recruiting --> Terminated; Sponsor's decision
    Enrollment change • Trial termination
    |
    HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    AL101
    10ms
    ACCURACY: A Study Of AL101In Patients With Adenoid Cystic Carcinoma (ACC) Bearing Activating Notch Mutations (clinicaltrials.gov)
    P2, N=87, Completed, Ayala Pharmaceuticals, Inc, | Active, not recruiting --> Completed
    Trial completion
    |
    AL101
    over1year
    AL101 therapy in patients with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC): Final ACCURACY trial results and meta-analysis of clinical outcomes (ESMO 2023)
    *Inverse variance method, no transformation, 0.5 continuity correction. ORR: CR + PR; DCR: CR + PR + SD Conclusions AL101 showed acceptable safety and tolerability in ACC pts with Notchmut and a response rate comparable to pooled estimates for available therapies in pts regardless of Notch status.
    Clinical data • Retrospective data • Metastases
    |
    NOTCH1 (Notch 1)
    |
    NOTCH mutation
    |
    AL101
    over1year
    Efficacy of NOTCH inhibitors (Ni) relative to prior systemic therapy or observation in patients (pts) with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) (ESMO 2023)
    Ni included AL101, a gamma-secretase inhibitor, or OMP-52M51, an antibody targeting N1...The efficacy of Ni compares favorably with efficacy of systemic therapies administered prior to Ni. The limited PFS and high rate of tumor progression on non-target lesions suggests Ni combination therapy may be necessary to address ACC heterogeneity.
    Clinical • Metastases
    |
    NOTCH1 (Notch 1)
    |
    AL101 • brontictuzumab (OMP-52M51)
    over2years
    AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling. (PubMed, Cell Death Dis)
    Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.
    Journal
    |
    NOTCH1 (Notch 1)
    |
    NOTCH1 mutation • NOTCH mutation
    |
    AL101
    over2years
    TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov)
    P2, N=67, Active, not recruiting, Ayala Pharmaceuticals, Inc, | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    AL101
    over2years
    Genetic heterogeneity and therapeutic target detection through microdissection in solid-type adenoid cystic carcinoma. (PubMed, Pathology)
    Guided by the genetic profiles, the preclinical efficiency of the gamma-secretase inhibitor BMS-906024 was evaluated in patient derived xenograft models (PDXs) with activating NOTCH1 mutations and demonstrated robust antitumour effects...In contrast to cribriform/tubular ACCs, solid-type ACCs should be approached with a distinct therapeutic strategy, particularly targeting NOTCH1. Microdissecting the highest grade component guided by histology is a highly recommended tumour sampling strategy and facilitates the detection of key molecular targets.
    Journal • BRCA Biomarker
    |
    BRCA2 (Breast cancer 2, early onset) • FGFR2 (Fibroblast growth factor receptor 2) • NOTCH1 (Notch 1) • NOTCH2 (Notch 2) • BCOR (BCL6 Corepressor) • NICD (NOTCH1 intracellular domain)
    |
    BRCA2 mutation • FGFR2 mutation • NOTCH1 mutation • BCOR mutation • NICD expression
    |
    AL101
    almost3years
    Preparation of Notch-4 Receptor Containing Quartz Crystal Microbalance Biosensor for MDA MB 231 Cancer Cell Detection. (PubMed, Methods Mol Biol)
    Here, we present the preparation methods of QCM-based sensors for selective detection of MDA MB 231 cancer cells. Selectivity of QCM-based sensor is carried out in the presence of L929 mouse fibroblast cells.
    Journal
    |
    NOTCH4 (Notch 4)
    3years
    Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases. (PubMed, Curr Oncol)
    Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.
    Clinical • Journal
    |
    CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    AL101 • varegacestat (AL102)
    over3years
    NOTCH Single Nucleotide Polymorphisms in the Predisposition of Breast and Colorectal Cancers in Saudi Patients. (PubMed, Pathol Oncol Res)
    Interestingly, the rs1043994 located in NOTCH3 showed gender preference and was found to be significantly associated with colorectal cancers in males. Validation of these findings in bigger populations of different ethnicities may prove beneficial in identifying rs11249433 and rs1043994 as genetic screening markers for early detection of breast and colorectal carcinomas, respectively.
    Clinical • Journal
    |
    NOTCH1 (Notch 1) • NOTCH2 (Notch 2) • NOTCH3 (Notch Receptor 3) • NOTCH4 (Notch 4)
    4years
    TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov)
    P2, N=67, Recruiting, Ayala Pharmaceuticals, Inc, | Not yet recruiting --> Recruiting
    Clinical • Enrollment open
    |
    HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    AL101
    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
    TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov)
    P2, N=67, Not yet recruiting, Ayala Pharmaceuticals, Inc,
    Clinical • New P2 trial
    |
    HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    AL101
    over4years
    Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway. (PubMed, Sci Rep)
    Finally, C-B or C-I inhibited tumor xenograft growth in nude mice and decreased the expression of CSC-markers and notch signaling proteins in tumor tissues. Together, our study suggests that C-B and C-I inhibit colon cancer growth by inhibiting Notch signaling pathway.
    Journal
    |
    NOTCH1 (Notch 1) • CD44 (CD44 Molecule) • HES1 (Hes Family BHLH Transcription Factor 1)
    over4years
    Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome. (PubMed, J Oncol)
    Patients overexpressing Notch3, Notch4, and Hey1 had significantly poorer overall survival relative to those having lower levels of these genes. Taken together, Notch signaling components are aberrantly overexpressed in colorectal tumors, and development of therapeutics targeting the Notch pathway may prove to be beneficial in the management of colorectal cancers.
    Clinical • Journal
    |
    NOTCH1 (Notch 1) • NOTCH4 (Notch 4) • HES1 (Hes Family BHLH Transcription Factor 1)