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DRUG:

alvocidib (DSP-2033)

i
Other names: DSP-2033, flHMR-1275, L868275, HL-275, HMR 1275, MDL-107826A, IND 46211, L 868275, NSC 649890
Company:
Sumitomo Pharma
Drug class:
CDK4 inhibitor, CDK6 inhibitor, CDK9 inhibitor
13d
Flavopiridol induces cell cycle arrest and apoptosis by interfering with CDK1 signaling pathway in human ovarian granulosa cells. (PubMed, Sci Rep)
FP reduced cell proliferation and induced apoptosis by inducing mitochondrial dysfunction and oxidative stress, as well as increasing BAX/BCL2 and pCDK1 levels. These results suggest that toxicity to the reproductive system should be considered when FP is used in clinical applications.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • BAX (BCL2-associated X protein) • CDK1 (Cyclin-dependent kinase 1)
|
alvocidib (DSP-2033)
2ms
RNA sequencing identifies lung cancer lineage and facilitates drug repositioning. (PubMed, PeerJ)
Our results indicated that dinaciclib and alvocidib exhibited similar activity and sensitivity in the neuroendocrine cluster. Also, a lineage factor named KLF5 recognized by inferred transcriptional factors activity could be suppressed by verteporfin.
Journal • IO biomarker
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STK11 (Serine/threonine kinase 11)
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STK11 mutation
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Visudyne (verteporfin) • alvocidib (DSP-2033) • dinaciclib (MK-7965)
2ms
Expression, potential biological behaviour and clinical significance of MCM3 in pancreatic adenocarcinoma: a comprehensive study integrating high throughput sequencing, CRISPR screening and in-house immunohistochemistry. (PubMed, Ann Med)
PAAD with high MCM3 expression was sensitive to c-75, brivanib, flavopiridol and VNLG/124 drugs, with stable molecular docking models. MCM3 is likely to be a critical element in promoting the initiation and growth of PAAD. Flavopiridol may exert its anti-PAAD effect through the interaction between MCM3, classic CDK1 targets in the cell cycle checkpoint and p53 pathway as well as related molecules in other pathways.
Journal
|
CDK1 (Cyclin-dependent kinase 1) • MCM3 (Minichromosome maintenance complex component 3)
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alvocidib (DSP-2033) • brivanib alaninate (BMS-582664)
2ms
Flavopiridol inhibits adipogenesis and improves metabolic homeostasis by ameliorating adipose tissue inflammation in a diet-induced obesity model. (PubMed, Biomed Pharmacother)
In the mouse model of diet-induced obesity, flavopiridol attenuated obesity-associated adipose tissue inflammation and improved serum lipid profile, glucose tolerance as well as insulin sensitivity. In conclusion, the FDA approved drug flavopiridol could be placed as a potential drug candidate for the treatment of cancer and obesity comorbid patients.
Journal
|
CEBPA (CCAAT Enhancer Binding Protein Alpha) • FASN (Fatty acid synthase) • PPARG (Peroxisome Proliferator Activated Receptor Gamma)
|
alvocidib (DSP-2033)
3ms
Investigating the molecular mechanism of vitexin targeting CDK1 to inhibit colon cancer cell proliferation via GEO chip data mining, computer simulation, and biological activity verification. (PubMed, Naunyn Schmiedebergs Arch Pharmacol)
Molecular docking revealed a strong interaction between Vitexin and CDK1 (Docking score - 9.497), with molecular dynamics simulations confirming the stability of the Vitexin-CDK1 complex and comparable inhibitory effects to Flavopiridol. Vitexin can inhibit the expression of CDK1/cyclin B proteins in HCT-116 cells, with an IC50 of 58.06 ± 3.07 μmol/L. Vitexin may inhibit colon cancer HCT-116 cell proliferation by suppressing CDK1/cyclin B expression, leading to cell cycle arrest in the G2/M phase.
Journal
|
CDK1 (Cyclin-dependent kinase 1)
|
alvocidib (DSP-2033)
5ms
Discovery of colchicine aryne cycloadduct as a potent molecule for the abrogation of epithelial to mesenchymal transition via modulating cell cycle regulatory CDK-2 and CDK-4 kinases in breast cancer cells. (PubMed, Bioorg Chem)
Additionally, B-4a displayed a noteworthy impact on tubulin polymerization, compared to positive control flavopiridol hydrochloride in a dose-dependent manner, and significantly disrupted the vimentin cytoskeleton, contributing to G1 arrest in breast cancer cells. Moreover, B-4a exhibited substantial anti-metastatic properties by inhibiting breast cancer cell migration and invasion. These effects are attributed to the down-regulation of major epithelial to mesenchymal transition (EMT) factors, including vimentin and Twist-1, and the upregulation of the epithelial marker E-cadherin in an apoptosis-dependent manner.
Journal
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CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • CDH1 (Cadherin 1) • VIM (Vimentin) • CDK2 (Cyclin-dependent kinase 2) • CCNB1 (Cyclin B1)
|
alvocidib (DSP-2033)
5ms
Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos. (PubMed, PLoS Genet)
In addition, cotreatment with Venetoclax and Flavopiridol significantly reduced the expression of endogenous mcl1a compared to vehicle, consist with AML. This new model of MLL-r-AML provides a novel tool to understand the molecular mechanisms underlying disease progression and a platform for drug discovery.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CDK9 (Cyclin Dependent Kinase 9)
|
Venclexta (venetoclax) • alvocidib (DSP-2033)
8ms
Enhanced Anti-tumor Effect of Flavopiridol in Combination With Gemcitabine in Pancreatic Cancer. (PubMed, Anticancer Res)
Flavopiridol potentiates the anti-tumor activity of gemcitabine by inducing cell cycle arrest and apoptosis. Its synergistic inhibition of PDAC cell proliferation, when combined with gemcitabine, positions flavopiridol as a promising candidate for cancer treatment.
Journal • Combination therapy
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CCNA2 (Cyclin A2) • CDK2 (Cyclin-dependent kinase 2)
|
CDK2 expression
|
gemcitabine • alvocidib (DSP-2033)
11ms
Comprehensive Profiling and Therapeutic Insights into Differentially Expressed Genes in Hepatocellular Carcinoma. (PubMed, Cancers (Basel))
Potential therapeutic chemicals are alvocidib, AT-7519, kenpaullone, PHA-793887, JNJ-7706621, danusertibe, doxorubicin and analogues, mitoxantrone, podofilox, teniposide, and amonafide. This multi-omic study offers a comprehensive view of DEGs in HCC, shedding light on potential therapeutic targets and drug repurposing opportunities.
Journal
|
TOP2A (DNA topoisomerase 2-alpha) • AURKA (Aurora kinase A) • RRM2 (Ribonucleotide Reductase Regulatory Subunit M2) • CDK1 (Cyclin-dependent kinase 1) • CCNB1 (Cyclin B1)
|
doxorubicin hydrochloride • mitoxantrone • alvocidib (DSP-2033) • Vumon (teniposide) • PHA 793887 • AT7519 • Quinamed (amonafide) • danusertib (PHA-739358)
12ms
Exploring the Mechanisms of Venetoclax Resistance Via Drug Screening and Genome-Wide CRISPR Screening (ASH 2023)
Among these hits, CDK2 correlates with our drug screening data indicating Flavopiridol as an effective compound in treating VeR cell lines. Integrating a range of screening approaches may lead to discovering previously unknown therapeutic targets for venetoclax-resistant AML. Our screens confirmed previously described involvement of the apoptotic pathway genes in venetoclax resistance as well as identified some novel promising targets. Our ongoing efforts involve thorough validations of the identified hits from CRISPR and drug screening to enhance the reliability and translatability of the results.
IO biomarker
|
TP53 (Tumor protein P53) • CDK2 (Cyclin-dependent kinase 2) • ELAVL1 (ELAV Like RNA Binding Protein 1)
|
Venclexta (venetoclax) • alvocidib (DSP-2033)
1year
ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms. (PubMed, Haematologica)
The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • ASXL1 (ASXL Transcriptional Regulator 1) • MCL1 (Myeloid cell leukemia 1) • CDK9 (Cyclin Dependent Kinase 9)
|
ASXL1 mutation • ASXL1 Y588X
|
azacitidine • alvocidib (DSP-2033)
1year
Analysis of some flavonoids for inhibitory mechanism against cancer target phosphatidylinositol 3-kinase (PI3K) using computational tool. (PubMed, Front Pharmacol)
Based on the above results, the stability of the most promising ligand, flavopiridol, against PI3Kγ was evaluated by molecular dynamics simulations for 200 ns, confirming the stable flavopiridol and PI3Kγ complex. Our study suggests that among the selected flavonoids specifically flavopiridol may act as potential inhibitors of PI3Kγ and could be a therapeutic alternative to inhibit the PI3Kγ pathway, providing new insights into rational drug discovery research for cancer therapy.
Journal
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PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma)
|
alvocidib (DSP-2033)
1year
Inhibition of GCN2 Reveals Synergy with Cell-Cycle Regulation and Proteostasis. (PubMed, Metabolites)
Inhibitors of proteostasis and the MEK-ERK pathway, as well as the pan-CDK inhibitors, flavopiridol, and seliciclib, were potently synergistic with TAP20 in two cell lines. However, TAP20 alone was sufficient to restrict invasion at concentrations well below its growth-inhibitory IC. We conclude that GCN2 inhibition can be further explored in vivo as a cancer target.
Journal
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CDK7 (Cyclin Dependent Kinase 7)
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alvocidib (DSP-2033) • seliciclib (CYC202)
1year
Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach. (PubMed, Oncol Res)
Thus, hub genes can be targeted with Alvocidib, Estradiol, Tretinoin, Capsaicin, Dronabinol, Metribolone, Calcitriol, Acetaminophen, Acitretin, Cyclosporine, Azacitidine, Genistein, and Resveratrol drugs. As the pathogenesis of KIRC is complex, targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance, which might uplift overall survival among KIRC patients.
Preclinical • Journal
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PTEN (Phosphatase and tensin homolog) • CCND1 (Cyclin D1) • MCL1 (Myeloid cell leukemia 1)
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cisplatin • azacitidine • alvocidib (DSP-2033) • dronabinol oral
1year
Computational drug prediction in hepatoblastoma by integrating pan-cancer transcriptomics with pharmacological response. (PubMed, Hepatology)
We thus identified two CDK9 inhibitors, alvocidib and dinaciclib as potent HB growth inhibitors for the high-risk C2 molecular subtype. We also found that in a cohort of 46 patients with HB, high CDK9 tumour expression was significantly associated with poor prognosis. Our work proves the usefulness of computational methods trained on pan-cancer datasets to reposition drugs in rare paediatric cancers such as HB, and to help clinicians in choosing the best treatment options for their patients.
Journal • Pan tumor
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alvocidib (DSP-2033) • dinaciclib (MK-7965)
1year
Flavopiridol Suppresses Cell Proliferation and Migration and Induces Apoptotic Cell Death by Inhibiting Oncogenic FOXM1 Signaling in IDH Wild-Type and IDH-Mutant GBM Cells. (PubMed, Mol Neurobiol)
Our findings suggest for the first time that flavopiridol suppresses proliferation, survival, and migration and induces apoptosis in IDH1 wild-type and IDH1-mutant GBM cells by targeting FOXM1 oncogenic signaling which also regulates NF-B, PARP, and UPR response in GBM cells. Flavopiridol may be a potential novel therapeutic strategy in the treatment of patients IDH1 wild-type and IDH1-mutant GBM.
Journal • PARP Biomarker
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • FOXM1 (Forkhead Box M1) • HSPA5 (Heat Shock Protein Family A (Hsp70) Member 5)
|
IDH1 mutation • IDH wild-type
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alvocidib (DSP-2033)
over1year
Patient-derived zebrafish xenografts of uveal melanoma reveal ferroptosis as a drug target. (PubMed, Cell Death Discov)
Metastasis formation could be reduced by navitoclax and more efficiently by the combinations navitoclax/everolimus and flavopiridol/quisinostat. Importantly, the ferroptosis-related genes GPX4 and SLC7A11 are negatively correlated with the survival of UM patients (TCGA: n = 80; Leiden University Medical Centre cohort: n = 64), ferroptosis susceptibility is correlated with loss of BAP1, one of the key prognosticators for metastatic UM, and ferroptosis induction greatly reduced metastasis formation in the UM xenograft model. Collectively, we have established a patient-derived animal model for metastatic UM and identified ferroptosis induction as a possible therapeutic strategy for the treatment of UM patients.
Journal
|
BAP1 (BRCA1 Associated Protein 1) • GPX4 (Glutathione Peroxidase 4) • SLC7A11 (Solute Carrier Family 7 Member 11)
|
everolimus • navitoclax (ABT 263) • alvocidib (DSP-2033) • quisinostat (JNJ 26481585)
over1year
A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. (PubMed, Hematol Oncol)
A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population.
P1 data • Journal
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Venclexta (venetoclax) • alvocidib (DSP-2033)
over1year
Phase 1 dose-expansion study of oral TP-1287, a cyclin-dependent kinase 9 (CDK9) inhibitor, in patients with Ewing sarcoma (EWS). (ASCO 2023)
TP-1287 is an investigational orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. EWS dose expansion cohort is currently recruiting in the United States. Clinical trial information: NCT03604783.
Clinical • P1 data
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MCL1 (Myeloid cell leukemia 1) • CDK9 (Cyclin Dependent Kinase 9)
|
MYC overexpression • MYC expression • MCL1 expression • CDK9 overexpression
|
alvocidib (DSP-2033) • TP-1287
over1year
Inhibition of multiple CDKs potentiates colon cancer chemotherapy via p73-mediated DR5 induction. (PubMed, Oncogene)
We found that less-selective CDKIs, including flavopiridol, roscovitine, dinaciclib, and SNS-032, induced DR5 via p73-mediated transcriptional activation...CDKIs strongly synergized with 5-fluorouracil (5-FU), the most commonly used CRC chemotherapy agent, in vitro and in vivo to promote growth suppression and apoptosis, which required DR5 and p73. Together, these findings indicate p73-mediated DR5 induction as a potential tumor suppressive mechanism and a critical target engaged by different CDKIs in potentiating therapy-induced apoptosis in CRC cells. These findings help better understand the anticancer mechanisms of CDKIs and may help facilitate their clinical development and applications in CRC.
Journal
|
CDK1 (Cyclin-dependent kinase 1) • TNFRSF10B (TNF Receptor Superfamily Member 10b)
|
5-fluorouracil • alvocidib (DSP-2033) • SNS-032 • dinaciclib (MK-7965) • seliciclib (CYC202)
over1year
Venetoclax and dinaciclib elicit synergisticpreclinicalefficacy against high-risk B-cell leukemia (AACR 2023)
In summary, our study identified a highly synergistic drug combination, venetoclax and dinaciclib, for the treatment of hypodiploid B ALL, an aggressive leukemia with few effective current therapies. Finally, the promising results presented in this study may prompt further studies to support the inclusion of hypodiploid and other B-ALL patients to clinical trials combining phase I/II drugs against BCL-2 (mainly venetoclax) and CDK9 (dinaciclib, alvocidib, flavopiridol, SNS-032) or MCL-1 (MIK-665).
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • CDK9 (Cyclin Dependent Kinase 9)
|
Venclexta (venetoclax) • alvocidib (DSP-2033) • SNS-032 • dinaciclib (MK-7965) • MIK665
over1year
Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors. (PubMed, Heliyon)
The chromone alkaloids, majorly rohitukine and its analogues were closely clustered with flavopiridol, P-276-00 and IIIM-290 along with other chrotacumines in the chemical phylogeny. In conclusion, D. binectariferum is a rich source of chromone alkaloids, which could lead to the discovery of more potential scaffolding for CDK inhibitors as anticancer drugs.
Journal
|
CDK1 (Cyclin-dependent kinase 1) • CDK15 (Cyclin Dependent Kinase 15)
|
alvocidib (DSP-2033) • riviciclib (P27600)
almost2years
RNA Polymerase I inhibitors for cancer therapy (LCC 2023)
To address the need for improved Pol I inhibitors with minimal off-target effects we collaborated with Pimera Inc to develop a selective 2nd-generation Pol I inhibitor, PMR-116. We show that combinatorial therapy with CX-5461 and both Flavopiridol and Dinaciclib have a synergistic effect in vitro and significantly increase the survival of acute myeloid leukaemia (AML) models in vivo. Our data indicates that inhibition of both Pol I (by CX-5461) and Pol II (by CDK9 inhibitors) can be used in as a therapy to extend survival and reduce acquired resistance.
BRCA Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
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pidnarulex (CX-5461) • alvocidib (DSP-2033) • dinaciclib (MK-7965) • PMR-116
almost2years
The Expression of Cell Cycle-Related Genes in USP8-Mutated Corticotroph Neuroendocrine Pituitary Tumors and Their Possible Role in Cell Cycle-Targeting Treatment. (PubMed, Cancers (Basel))
We looked for the role of USP8 mutations or a changed p27 level in the response to palbociclib, flavopiridol and roscovitine in vitro using murine corticotroph AtT-20/D16v-F2 cells. Overexpression of mutated Usp8 in the cells did not affect the expression of p27 nor the response to the inhibitors. Downregulating or upregulating p27 expression in AtT-20/D16v-F2 cells also did not affect treatment response.
Journal
|
CCND1 (Cyclin D1) • CDK6 (Cyclin-dependent kinase 6) • CCND2 (Cyclin D2) • CDKN1B (Cyclin dependent kinase inhibitor 1B) • CDC25A (Cell Division Cycle 25A) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)
|
CCND1 expression • CDKN1B expression
|
Ibrance (palbociclib) • alvocidib (DSP-2033) • seliciclib (CYC202)
almost2years
Cyclin D1 mediates pain behaviour in a rat model of breast cancer-induced bone pain by a mechanism involving regulation of the proliferation of spinal microglia. (PubMed, Bone Joint Res)
Our results revealed that the inhibition of spinal microglial proliferation was associated with a decrease in pain behaviour in a rat model of BCP. Cyclin D1 acts as a key regulator of the proliferation of spinal microglia in a rat model of BCP. Disruption of cyclin D1, the restriction-point control of cell cycle, inhibited the proliferation of microglia and attenuated the pain behaviours in BCP rats. Cyclin D1 and the proliferation of spinal microglia may be potential targets for the clinical treatment of BCP.Cite this article: Bone Joint Res 2022;11(11):803-813.
Preclinical • Journal
|
CCND1 (Cyclin D1)
|
CCND1 expression
|
alvocidib (DSP-2033)
2years
ASXL1 Mutations Are Associated with a Response to the Combination of Alvocidib and 5-Azacytidine in Higher-Risk Myelodysplastic Syndromes (ASH 2022)
A phase 1b/2 study with Alv and HMAs 5-Azacytidine (5-AZA) or decitabine in higher-risk MDS patients was recently completed (NCT03593915). We provided a pre-clinical rationale for the use of the 5-AZA+Alv combination for higher risks MDS and proposed ASXL1 mutations as potential genetic biomarkers of response in prospective clinical trials.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • ASXL1 (ASXL Transcriptional Regulator 1) • MCL1 (Myeloid cell leukemia 1) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CDK9 (Cyclin Dependent Kinase 9) • ANXA5 (Annexin A5)
|
ASXL1 mutation • MCL1 expression • ASXL1 Y588X
|
azacitidine • decitabine • alvocidib (DSP-2033)
2years
c-myb is involved in CML progression and is a therapeutic target in the zebrafish CML model. (PubMed, Animal Model Exp Med)
In summary, this study suggests that c-myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression. The model used in the study could be helpful in high-throughput drug screening in CML transformation.
Journal
|
ABL1 (ABL proto-oncogene 1) • MYB (MYB Proto-Oncogene, Transcription Factor)
|
imatinib • alvocidib (DSP-2033)
2years
Novel benzylidene benzofuranone analogues as potential anticancer agents: design, synthesis and in vitro evaluation based on CDK2 inhibition assays. (PubMed, 3 Biotech)
Flavopiridol is one such drug candidate...However, the compound NISOA4 along with other analogues showed appreciable inhibition for the CDK2/Cyclin A target enzyme. The online version contains supplementary material available at 10.1007/s13205-022-03312-1.
Preclinical • Journal
|
CCNA2 (Cyclin A2)
|
CDK2 expression
|
alvocidib (DSP-2033)
2years
Alvocidib inhibits IRF4 expression via super-enhancer suppression and adult T-cell leukemia/lymphoma cell growth. (PubMed, Cancer Sci)
Hence, the present work demonstrated that alvocidib has therapeutic efficacy against ATL and partially elucidated its mode of action. It also showed that alvocidib is promising for the clinical treatment of ATL and perhaps other malignancies and neoplasms as well.
Journal
|
IRF4 (Interferon regulatory factor 4)
|
IRF4 expression
|
alvocidib (DSP-2033)
over2years
A validated LC-MS/MS analytical method for the quantification of pemigatinib: metabolic stability evaluation in human liver microsomes. (PubMed, RSC Adv)
PMB and flavopiridol (FVL), used as an internal standard IS, were resolved using an isocratic mobile phase and a C18 stationary phase. PMB showed a moderate extraction ratio suggesting good bioavailability. The developed analytical method is the first LC-MS/MS method specific for PMB quantification with application to metabolic stability assessment.
Journal
|
FGFR2 (Fibroblast growth factor receptor 2) • FGFR3 (Fibroblast growth factor receptor 3) • FGFR1 (Fibroblast growth factor receptor 1)
|
FGFR2 fusion
|
Pemazyre (pemigatinib) • alvocidib (DSP-2033)
over2years
Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan. (PubMed, Cancer Sci)
Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov: NCT03563560.
P1 data • Journal
|
CDK9 (Cyclin Dependent Kinase 9)
|
cytarabine • daunorubicin • mitoxantrone • alvocidib (DSP-2033)
over2years
VIP152 IS A NOVEL CDK9 INHIBITOR WITH IMPROVED SELECTIVITY, TARGET MODULATION, AND CARDIAC SAFETY IN PATIENTS WITH LYMPHOMA (EHA 2022)
To demonstrate the utility of a selective CDK9 inhibitor for treatment of hematologic patients with an unmet medical need such as high-grade B cell lymphoma (HGBL) and chronic lymphocytic leukemia who relapse or are refractory to ibrutinib and venetoclax (R/R CLL)...Differential expression (DE) analysis from VIP152, atuveciclib and KB-0742 treatment of 2 lymphoma cell lines by RNA seq is compared to DE of samples from 7 VIP152 treated HGBL patients...With high ATP, VIP152, AZD4573 and alvocidib maintain potency in low nM range, while fadraciclib and KB-0742 have 760 nM-1.7 µM IC50s...Selective transcriptional downregulation is observed with 30mg IV weekly. Samples from patients with DLBCL or CLL are sensitive to VIP152 and updated PK, PD and ctDNA dynamics from the ongoing phase 1 trials (NCT02635672, NCT04978779) will be presented.
Clinical
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 R175H • TP53 R248Q
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • alvocidib (DSP-2033) • istisociclib (KB-0742) • fadraciclib (CYC065) • enitociclib (VIP152) • AZD4573 • atuveciclib (BAY 1143572)
over2years
IMAGE-BASED HIGH-CONTENT DRUG SENSITIVITY SCREENING IDENTIFIES CONVENTIONAL, EMERGING, AND POTENTIAL NOVEL THERAPEUTIC TARGETS IN HIGH-RISK ADULT ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2022)
These included pan-CDK family inhibitors alvocidib, CGP60474, and roscovitine-derived CR8. Conclusion We provide evidence that high-content drug screening in a co-culture system is an effective strategy to identify clinically-relevant novel and emerging therapeutic targets in high-risk ALL. Our analyses promote a strong rationale for exploring the targeting of CDKs as a potential pan-effective approach in high-risk adult ALL.
Clinical
|
NAMPT (Nicotinamide Phosphoribosyltransferase)
|
alvocidib (DSP-2033) • seliciclib (CYC202)
over2years
Mutations in the ASXL1 and ZRSR2 genes are associated with the response to the combination of alvocidib and 5-azacytidine in higher-risk myelodysplastic syndromes (AACR 2022)
A phase 1b/2 study with Alv and 5-Aza or decitabine in higher-risk patients with MDS was recently completed (NCT03593915); however, biomarkers for response to the Alv and 5-Aza combination are not well characterized. ZRSR2 mutations also retained an independent impact on cell viability in multivariable analysis (p=0.035). Overall, we provide pre-clinical support for the use of 5-Aza+Alv combination for higher-risk MDS and identified ASXL1 and ZRSR2 mutations as potential genetic biomarkers of augmented response.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • ASXL1 (ASXL Transcriptional Regulator 1) • MCL1 (Myeloid cell leukemia 1) • CD34 (CD34 molecule) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
|
ASXL1 mutation • ZRSR2 mutation
|
azacitidine • decitabine • alvocidib (DSP-2033)
over2years
Case study of single-cell protein activity-based drug prediction and validation for precision treatment of cholangiocarcinoma (AACR 2022)
Consensus OTar/OTr drug prediction analysis on both scRNASeq tumor cells and bulk RNA-Seq of an engrafted PDX model from resected tumor at the time of biopsy ranked Glasdegib, Plicamycin, Flavopiridol, AT9283, and Dacinostat as the top 5 drugs with best overall tumor cell coverage. Both of these drugs significantly extended survival time by Kaplan-Meier regression (p=0.001 and p=0.03, respectively). Furthermore, scRNASeq data of drug-treated PDXs showed that Dacinostat uniformly depleted all three tumor sub-populations compared to Vehicle control, whereas one of the tumor sub-clusters was resistant to Plicamycin, consistent with single-cell drug sensitivity predicted by OTr.Given the in vivo activity of these two drugs in inhibiting tumor growth, and the effectiveness of Dacinostat across observed tumor cell phenotypes, as well as the high immune infiltration of this CCA sample, these drugs may be translated into pre-clinical and clinical trials alone and in combination with checkpoint immunotherapy.
Clinical • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • TNFA (Tumor Necrosis Factor-Alpha)
|
alvocidib (DSP-2033) • Daurismo (glasdegib) • AT9283
over2years
Examining the potential therapeutic efficacy of the CDK inhibitor alvocidib in a pre-clinical model of myelodysplastic syndrome (AACR 2022)
In addition to alvocidib, we evaluated the in vitro efficacy of 5-Azacytidine (5-Aza) and Decitabine (DAC), which are hypomethylating agents used in treatment of MDS. This type of dramatic response has not previously been observed in over 20 prior chimeric transplant experiments employing the NHD13 mouse model. Ongoing efforts include follow-up studies to evaluate the frequency of exceptional responders, as well as identification of acquired mutations which collaborate with the initiating mutation (NHD13) to generate AML.
Preclinical
|
NUP98 (Nucleoporin 98 And 96 Precursor 2) • CDK9 (Cyclin Dependent Kinase 9)
|
azacitidine • decitabine • alvocidib (DSP-2033)
over2years
CDK9 as a potential therapeutic target in sarcomas (AACR 2022)
Taken together, alvocidib has shown activity in inhibiting the growth of sarcoma cells and TP-1287 could be a viable therapeutic option targeting the CDK9 pathway in sarcomas. TP-1287 is being investigated for solid tumors including sarcomas (clinicaltrials.gov, NCT03604783).
PARP Biomarker
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MCL1 (Myeloid cell leukemia 1) • CASP3 (Caspase 3) • CDK9 (Cyclin Dependent Kinase 9) • CASP7 (Caspase 7)
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MCL1 expression
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alvocidib (DSP-2033) • TP-1287
over2years
Phase 1, first-in-human, dose-escalation study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients (pts) with advanced solid tumors (ASTs) (AACR 2022)
TP-1287 is an orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. The RP2D was established as 11 mg BID continuous dosing. The dose expansion cohort is open for enrollment.Table. Safety >
Clinical • P1 data
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CDK9 (Cyclin Dependent Kinase 9)
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alvocidib (DSP-2033) • TP-1287
almost3years
Drug repositioning based on gene expression data for human HER2-positive breast cancer. (PubMed, Arch Biochem Biophys)
According to the obtained results, some of these drugs including vorinostat, mocetinostat, alvocidib, CGP-60474, BMS-387032, AT-7519, and curcumin have significant functional similarity and structural correlation with FDA-approved breast cancer drugs. Moreover, the experimental approach verified curcumin as an effective therapeutic agent for HER2 positive breast cancer. Hence, our work suggested that some repurposed drugs based on gene expression data can be noticed as potential drugs for the treatment of HER2-positive breast cancer.
Journal
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HER-2 (Human epidermal growth factor receptor 2)
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HER-2 positive • HER-2 expression
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Zolinza (vorinostat) • alvocidib (DSP-2033) • SNS-032 • mocetinostat (MGCD0103) • AT7519