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DRUG:

BTX-A51

i
Other names: BTX-A51
Company:
Edgewood Oncology
Drug class:
CDK9 inhibitor, CDK7 inhibitor, p53 stimulant, Casein kinase 1 alpha inhibitor
21d
Phase I First-in-Human Dose Escalation Study of the oral Casein Kinase 1α and Cyclin Dependent Kinase 7/9 inhibitor BTX-A51 in advanced MDS and AML. (PubMed, Res Sq)
Ex-vivo studies confirmed higher efficacy of BTX-A51 on RUNX1 -mutated myeloblasts and demonstrate synergy with azacitidine and venetoclax. Although the overall efficacy was modest, this study lays the groundwork for future studies with improved patient selection and combination approaches.
P1 data • Journal • Metastases
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RUNX1 (RUNX Family Transcription Factor 1) • CDK7 (Cyclin Dependent Kinase 7)
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RUNX1 mutation • MCL1 expression • TP53 expression
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Venclexta (venetoclax) • azacitidine • BTX-A51
3ms
Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors. (PubMed, ACS Med Chem Lett)
Starting from BTX-A51, a CK1α inhibitor that also targets CDK7 and CDK9, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as potent CDK7 inhibitors...Compound 22 effectively inhibited the phosphorylation of RNA polymerase II and CDK2 and resulted in G1/S phase cell cycle arrest and apoptosis in MV4-11 cells. It appears to be a promising lead compound for the development of a CDK7 inhibitor for cancer therapy.
Journal
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CDK2 (Cyclin-dependent kinase 2) • CDK9 (Cyclin Dependent Kinase 9)
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BTX-A51
6ms
BTX-A51 in Patients With Liposarcoma (clinicaltrials.gov)
P1, N=12, Not yet recruiting, Michael Wagner
New P1 trial • Metastases
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BTX-A51
over2years
SAFETY AND EFFICACY OF CASEIN KINASE 1Α AND CYCLIN DEPENDENT KINASE 7/9 INHIBITION IN PATIENTS WITH RELAPSED OR REFRACTORY AML: A PHASE 1, FIRST-IN-HUMAN STUDY OF BTX-A51 (EHA 2022)
Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining >50% BM blast reduction.
Clinical • P1 data
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RUNX1 (RUNX Family Transcription Factor 1) • MCL1 (Myeloid cell leukemia 1) • MDM2 (E3 ubiquitin protein ligase) • CDK7 (Cyclin Dependent Kinase 7) • CDK9 (Cyclin Dependent Kinase 9)
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RUNX1 mutation • MCL1 expression
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Venclexta (venetoclax) • BTX-A51
over2years
Safety and efficacy of casein kinase 1α and cyclin dependent kinase 7/9 inhibition in patients with relapsed or refractory AML: A first-in-human study of BTX-A51. (ASCO 2022)
Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. In this FIH study, monotherapy BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining > 50% BM blast reduction.
Clinical • P1 data
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RUNX1 (RUNX Family Transcription Factor 1) • MCL1 (Myeloid cell leukemia 1) • CDK7 (Cyclin Dependent Kinase 7)
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RUNX1 mutation • MCL1 expression
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Venclexta (venetoclax) • BTX-A51
4years
[VIRTUAL] Trial in Progress: A Phase I Trial of BTX-A51 in Patients with Relapsed or Refractory AML or High-Risk MDS (ASH 2020)
The antiapoptotic gene Mcl1 is overexpressed in AML cell lines resistant to venetoclax...For the first cycle, patients will receive tumor lysis syndrome prophylaxis with allopurinol and intravenous fluids and be closely monitored...Key exclusion criteria are receipt of cancer chemotherapy (other than hydroxyurea) within 2 weeks prior to the start of study drug, transplantation within 3 months prior to screening, active graft-versus-host disease requiring systemic immunosuppressive medications, and a white blood cell count > 20 × 109/L...Correlative objectives include determining the changes in SEs and SE-driven expression of antiapoptotic genes by chromatin immunoprecipitation and RNA-sequencing. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT04243785
Clinical • P1 data
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TP53 (Tumor protein P53) • MCL1 (Myeloid cell leukemia 1) • MDM2 (E3 ubiquitin protein ligase) • CDK7 (Cyclin Dependent Kinase 7)
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TP53 mutation • MCL1 overexpression • TP53 expression
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Venclexta (venetoclax) • hydroxyurea • BTX-A51