^
    4d
    Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models. (PubMed, Sci Rep)
    Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.
    Preclinical • Journal
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    FLT3 (Fms-related tyrosine kinase 3) • CDK6 (Cyclin-dependent kinase 6) • CSF1R (Colony stimulating factor 1 receptor)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type
    |
    narazaciclib (HX301)
    5ms
    Study of ON 123300 in Patients With Advanced Cancer (clinicaltrials.gov)
    P1, N=36, Recruiting, Onconova Therapeutics, Inc. | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    narazaciclib (HX301)
    6ms
    Narazaciclib, a Differentiated CDK4/6 Antagonist, Prolongs Cell Cycle Arrest and Metabolomic Reprogramming, Enabling Restoration of Ibrutinib Sensitivity in Btki-Resistant Mantle Cell Lymphoma (ASH 2023)
    We compared the efficacy and safety profiles of narazaciclib with three health authority-approved CDKi (palbociclib, abemaciclib or ribociclib) in association with covalent (ibrutinib, acalabrutinib) and non-covalent (pirtobrutinib, ARQ-531) BTKi, across a panel of 10 MCL cell lines with distinct sensitivity to the first-in-class BTKi, ibrutinib. In conclusion, our findings demonstrate that narazaciclib is safe and effective as a single agent in preclinical models of MCL, including BTKi-resistant cases. Its combination with ibrutinib achieved a synergistic tumoricidal effect in vitro and in vivo, accelerating cell cycle blockade and reverting the metabolic reprogramming characterizing MCL refractoriness to BTKi therapy.
    Metabolomic study
    |
    CDK4 (Cyclin-dependent kinase 4) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    Ibrance (palbociclib) • Imbruvica (ibrutinib) • Verzenio (abemaciclib) • Kisqali (ribociclib) • Calquence (acalabrutinib) • Jaypirca (pirtobrutinib) • narazaciclib (HX301) • nemtabrutinib (MK-1026)
    7ms
    The Tolerability and Pharmacokinetics of HX301 Monolactate Capsules in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=20, Active, not recruiting, Hangzhou Hanx Biopharmaceuticals, Ltd. | Trial primary completion date: Apr 2023 --> Dec 2023
    Trial primary completion date • Metastases
    |
    PD-L1 (Programmed death ligand 1)
    |
    narazaciclib (HX301)
    12ms
    Prolonged cell cycle arrest by the CDK4/6 antagonist narazaciclib restores ibrutinib response in preclinical models of BTKi-resistant mantle cell lymphoma (ICML 2023)
    Previous studies have suggested that narazaciclib (ON123300), a second-generation, orally bioavailable and clinical-stage CDK4/6 inhibitor (CDKi), may trigger cell cycle arrest and significant tumor growth inhibition (TGI) in BTKi-resistant MCL models...When combined with ibrutinib, but not with the second generation therapeutic acalabrutinib, narazaciclib achieved significant synergistic antitumor activity in both BTK-sensitive and BTK-resistant cells... Narazaciclib, due to its completely distinct MoA from BTKi involving the direct modulation of the cell cycle, can achieve significant synergistic activity with ibrutinib in vitro and in vivo, especially in BTKi-resistant models of MCL. Ongoing phospho-proteomics and genetic edition assays will help deciphering the molecular bases of this unique drug cooperation at the cell cycle level. Encore Abstract - previously submitted to AACR 2023
    Preclinical
    |
    CDK4 (Cyclin-dependent kinase 4) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    Imbruvica (ibrutinib) • Calquence (acalabrutinib) • narazaciclib (HX301) • Undisclosed CDK4/6 inhibitor
    1year
    Study of Narazaciclib (ON 123300) Plus Letrozole in Recurrent Metastatic Low-grade Endometrioid Endometrial Cancer (clinicaltrials.gov)
    P1/2, N=60, Recruiting, Onconova Therapeutics, Inc. | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy • Metastases
    |
    PGR (Progesterone receptor)
    |
    MSI-H/dMMR
    |
    letrozole • narazaciclib (HX301)
    1year
    Differential targets engaged by narazaciclib in comparison to the approved CDK4/6 inhibitors contribute to enhanced inhibition of tumor cell growth (AACR 2023)
    Docking data showed a higher affinity of narazaciclib with BUB1 compared to palbociclib and abemaciclib. Combination of narazaciclib with autophagy inhibitors sensitized several breast cancer cells to cell death. Narazaciclib treatment may promote antitumor immunity by influencing the expression of various immune modulators in the tumor cells which needs to be further validated in preclinical animal models; and ultimately in the clinic.
    PD(L)-1 Biomarker • IO biomarker • Tumor cell
    |
    HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • B2M (Beta-2-microglobulin) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • AURKA (Aurora kinase A) • CHEK1 (Checkpoint kinase 1) • CSF1R (Colony stimulating factor 1 receptor) • BUB1 (BUB1 Mitotic Checkpoint Serine/Threonine Kinase)
    |
    HER-2 negative
    |
    Ibrance (palbociclib) • Verzenio (abemaciclib) • narazaciclib (HX301)
    1year
    HX301 (ON1232580) a novel kinase inhibitor with potent activity against CSF1R and FLT3, shows strong anti-AML activity in defined preclinical models (AACR 2023)
    HX301 also suppressed AM7577 growth, likely due to the suppression of FLT3-ITD activity since we previously reported FLT3-ITD being the driver mutation in this model which responded to AC220, a FLT3 TKi...Further preclinical/translational studies are being conducted in order to reveal predictive biomarkers, in addition to FLT3 mutation and CSF1R expression/mutations. We believe that HX301 could be a potential candidate for treating subset of AML, warranting further clinical investigation.
    Preclinical
    |
    FLT3 (Fms-related tyrosine kinase 3) • CSF1R (Colony stimulating factor 1 receptor)
    |
    FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type • FLT3 expression • FLT3-ITD expression
    |
    Vanflyta (quizartinib) • narazaciclib (HX301)
    1year
    The Tolerability and Pharmacokinetics of HX301 Monolactate Capsules in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=20, Active, not recruiting, Hangzhou Hanx Biopharmaceuticals, Ltd.
    New P1 trial • Metastases
    |
    PD-L1 (Programmed death ligand 1)
    |
    narazaciclib (HX301)
    1year
    Study of Narazaciclib (ON 123300) Plus Letrozole in Recurrent Metastatic Low-grade Endometrioid Endometrial Cancer (clinicaltrials.gov)
    P1/2, N=60, Not yet recruiting, Onconova Therapeutics, Inc.
    New P1/2 trial • Combination therapy • Metastases
    |
    PGR (Progesterone receptor)
    |
    MSI-H/dMMR
    |
    letrozole • narazaciclib (HX301)