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    DRUG CLASS:

    RNA polymerase 2 inhibitor

    Related drugs:
    14d
    Inhibition of RNA polymerase II-activating CDK9 and CDK12/13, but not of cell cycle relevant CDKs, induces apoptosis by downregulating the short-lived Bcl-2 proteins Mcl1 and Bfl1/A1. (PubMed, Cell Death Dis)
    Only inhibition of CDK9 (by AZD4573 and atuveciclib) or of CDK12/13 (by SR4835 and THZ531)-which target the transcriptional elongation of RNA polymerase II (RNAPII)-exerted a strong apoptotic potential. Because Bcl-2 only inhibits Bax, but not Bak, AZD4573 and SR4835 were able to induce apoptosis in Jurkat cells overexpressing Bcl-2. As tumor cells frequently upregulate Bcl-2, inhibitors of CDK9 and CDK12/13 represent promising anticancer drugs.
    Journal • IO biomarker
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    BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • CDK4 (Cyclin-dependent kinase 4) • BCL2L1 (BCL2-like 1) • CDK12 (Cyclin dependent kinase 12) • CDK7 (Cyclin Dependent Kinase 7) • CDK9 (Cyclin Dependent Kinase 9) • CDK1 (Cyclin-dependent kinase 1) • CDC73 (Cell Division Cycle 73)
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    zemirciclib (AZD4573) • atuveciclib (BAY 1143572)
    2ms
    Study to Assess Safety and Efficacy of HDP-101 in Chinese Patients With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov)
    P1, N=15, Recruiting, Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd.
    New P1 trial
    |
    pamlectabart tismanitin (HDP-101)
    2ms
    First-In-Human Study of KHN922 for Injection (clinicaltrials.gov)
    P1/2, N=276, Not yet recruiting, Chengdu Kanghong Biotech Co., Ltd.
    New P1/2 trial • First-in-human
    almost2years
    HDP-101-01: Study to Assess Safety of HDP-101 in Patients With Relapsed Refractory Multiple Myeloma (clinicaltrials.gov)
    P1/2, N=78, Recruiting, Heidelberg Pharma AG | Trial completion date: May 2025 --> May 2026 | Trial primary completion date: Aug 2024 --> Aug 2025
    Trial completion date • Trial primary completion date
    |
    pamlectabart tismanitin (HDP-101)
    2years
    A Study of LY4101174 in Participants With Recurrent, Advanced or Metastatic Solid Tumors (clinicaltrials.gov)
    P1, N=280, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    over2years
    Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate conditioned Fanconi anemia mice. (PubMed, Blood)
    Moreover, single dose anti-human CD45-ADC given to rhesus macaque nonhuman primates on days -6 or -10 was at least as myeloablative as lethal irradiation. These data suggest that CD45-ADC can potently promote donor alloengraftment and hematopoiesis without significant toxicity or severe GVHD, as seen with lethal irradiation, providing strong support for clinical trial considerations in highly vulnerable FA patients.
    Preclinical • Journal
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    FANCA (FA Complementation Group A) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • FANCG (FA Complementation Group G) • FANCC (FA Complementation Group C)
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    CD45-ADC
    over2years
    A Study of LY4101174 in Participants With Recurrent, Advanced or Metastatic Solid Tumors (clinicaltrials.gov)
    P1, N=280, Not yet recruiting, Eli Lilly and Company
    New P1 trial
    over2years
    Hdp-101, an Anti-BCMA Antibody-Drug Conjugate with a Novel Payload Amanitin in Patients with Relapsed Multiple Myeloma, Initial Findings of the First in Human Study (ASH 2023)
    Currently the study is enrolling patients in Cohort #4 at the dose of 80μg/Kg. Additional updates will be provided at the 2023 ASH Annual Meeting.
    Clinical • P1 data
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    SDC1 (Syndecan 1)
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    pamlectabart tismanitin (HDP-101)
    over2years
    CD117 Antibody-Drug Conjugate Conditioning Allows Efficient Engraftment of Gene-Modified CD34+ Cells with Fertility Preservation in a Rhesus Gene Therapy Model (ASH 2023)
    To investigate the activity of CD117-ADC in non-human primates, we administered a single injection of ADC without HSC infusion, resulting in a >99% depletion of CD34+CD90+ bone marrow cells in cynomolgus macaques (n=2 of 3 in 0.1 mg/kg and n=3 in 0.3 mg/kg); similar to the ablation observed with 4 doses of myeloablative busulfan (Bu) (n=3). The transplanted animals with ADC maintained their fertility. Overall, these data indicate that an ADC-based targeted approach offers safer conditioning and could improve the risk-benefit profile in HSC gene therapy.
    Gene therapy
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    KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD34 (CD34 molecule) • THY1 (Thy-1 membrane glycoprotein)
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    opelkibart elmanitin (MGTA-117) • busulfan