Dataset Information

Effect of CDK7 inhibitor on protein expression alterations in cultured secondary AML HEL92.1.7 cells

ABSTRACT: HEL92.1.7 cells in exponential growth phase were treated with 100 nM of SY-5609 for 24 hours to determine the global protein expression alterations that correlate with the cell cycle, growth inhibitory and lethal effects of treatment with a CDK7 inhibitor in secondary AML cells.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Antrix Jain

LAB HEAD: Kapil N. Bhalla

PROVIDER: PXD053572 | Pride | 2025-04-28

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	52301_1_EXP_1011_hs_TMT16_prof_plex1_250ng_F01.pepXML	Pepxml
	52301_1_EXP_1011_hs_TMT16_prof_plex1_250ng_F01.raw	Raw
	52301_1_EXP_1011_hs_TMT16_prof_plex1_250ng_F02.pepXML	Pepxml
	52301_1_EXP_1011_hs_TMT16_prof_plex1_250ng_F02.raw	Raw
	52301_1_EXP_1011_hs_TMT16_prof_plex1_250ng_F03.pepXML	Pepxml

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Publications

Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML.

Fiskus Warren W Mill Christopher P CP Bose Prithviraj P Masarova Lucia L Pemmaraju Naveen N Dunbar Andrew A Birdwell Christine E CE Davis John A JA Das Kaberi K Hou Hanxi H Manshouri Taghi T Jain Antrix A Malovannaya Anna A Philip Kevin K Alhamadani Noor N Matthews Alicia A Lin Katie K Flores Lauren B LB Loghavi Sanam S DiNardo Courtney C Su Xiaoping X Rampal Raajit K RK Bhalla Kapil N KN

Blood 20250201 6

<h4>Abstract</h4>Rising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK1/2 inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2, HEL and patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality w ...[more]

PMID: 39561280

Similar Datasets

Project description:Recent studies reveal that a subset of cancers in various indications are dependent on high and constant expression of certain transcription factors for growth and survival, a phenomenon termed as transcriptional addiction. Therefore, targeting transcriptional machinery can potentially lead to potent and selective anticancer effects. CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Its function is required for both cell cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive target in cancer since its inhibition leads to decrease of the transcript levels of oncogenic transcription factors, especially those associated with super-enhancers (SEs). Here we describe a first-in-class CDK7 inhibitor SY-1365, which covalently targets a cysteine outside the kinase domain, resulting in sustained, highly selective inhibition of CDK7. In vitro studies reveal that SY-1365 has potency in a wide range of cancer models with low micromolar IC50 values. Cancer cells with low BCL-XL expression are found to be more dependent on MCL1 for survival and therefore particularly sensitive towards SY-1365 treatment since SY-1365 downregulates MCL1 protein level. SY-1365 treatment induces distinct transcriptional changes in acute myeloid leukemia (AML) cell lines. SY-1365 also demonstrates substantial anti-tumor effects in multiple AML xenograft models. Additionally, combination treatment with venetoclax shows synergistic effects in AML models both in vitro and in vivo. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers. SY-1365 is currently being assessed in a Phase I trial in adult patients (NCT03134638) We performed microarray based expression profiling to quantify transcriptional changes upon treatment with the CDK7 inhibitor, SY-1365 and to compare it to transcriptional changes induced by treatment with other transcriptional drugs JQ1 (BRD4 inhibitor), NVP2 (CDK9 inhibitor) and flavopiridol (pan-CDK inhibitor). We profiled a human acute myeloid leukemia (AML) cell line THP-1. Cells were treated with either DMSO, 100nm SY-1365, 25nM NVP2 , 250nM JQ1 or 200nM flavopiridol for two and six hours. All samples were prepared in biological triplicate.