230MO First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies

Krebs, Matthew; Lord, Simon; Kenny, Louise C.; Baird, Richard D.; Macpherson, Iain; Bahl, Ash; Clack, Glen; Ainscow, Edward; Barrett, A.; Dickinson, P.; Fuchter, Matthew J.; Lehnert, Martina; Ali, Shahina; McIntosh, Stuart; Coombes, R. Charles

doi:10.1016/j.annonc.2021.08.513

Cited by 7 publications

(5 citation statements)

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“…CT7001 is currently in phase I/II clinical trials for advanced solid malignancies (NCT03363893). Recently released data from this study demonstrated acceptable safety profile and evidence of antitumour activity, including PSA reductions in 4 CRPC patients [ 33 , 34 ]. As CT7001 is currently undergoing clinical evaluation, a more comprehensive investigation of its preclinical activity in prostate cancer is warranted.…”

Section: Introductionmentioning

confidence: 99%

The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

et al. 2023

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Background Current strategies to inhibit androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription, providing a rationale for its therapeutic targeting in CRPC. Methods The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanisms driving CT7001 activity, alone and in combination with the antiandrogen enzalutamide. Results CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo. Conclusions This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.

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Section: Introductionmentioning

confidence: 99%

The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

et al. 2023

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“…CT7001 is currently in phase I/II clinical trials for advanced solid malignancies (NCT03363893). Recently released data from this study demonstrated acceptable safety profile and evidence of antitumour activity, including PSA reductions in 4 CRPC patients [31]. Notably, the combination of CT7001 with fulvestrant was well-tolerated and reduced tumour burden in a cohort of patients with CDK4/6 inhibitor-resistant/hormone receptor-positive/HER2-negative breast cancer [32].…”

Section: Introductionmentioning

confidence: 99%

The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

Constantin

Varela-Carver

Greenland

et al. 2022

Preprint

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Background: Current strategies to inhibit the androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription regulation, together, providing a rationale for its therapeutic targeting in CRPC. Methods: The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanism driving activity of CT7001, alone and in combination with the antiandrogen enzalutamide. Results: CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo. Conclusions: This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.

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“…This modification, however, did not significantly affect the selectivity. Moving the amino group to the 3-position on the cyclohexane ring (17) enhanced the activity by over 9-fold compared to 16. Replacement of the amino group with a hydroxyl group (18) slightly improved both the potency and the selectivity of compound 6.…”

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confidence: 98%

“…The second type of CDK7 inhibitors includes several noncovalent selective inhibitors such as BS-181, CT7001 (samuraciclib), SY-5609, and LDC4297 (Figure ). In a completed Phase 1 clinical study, CT7001 was well-tolerated and showed clinical activity in a variety of advanced solid tumor patients (NCT03363893) . Another promising drug currently undergoing clinical testing, SY-5609, has received FDA orphan drug designation for the treatment of pancreatic cancer.…”

mentioning

confidence: 99%

“…16 In a completed Phase 1 clinical study, CT7001 was well-tolerated and showed clinical activity in a variety of advanced solid tumor patients (NCT03363893). 17 Another promising drug currently undergoing clinical testing, SY-5609, has received FDA orphan drug designation for the treatment of pancreatic cancer. These together suggest that the inhibition of CDK7 in cancers is an attractive strategy for drug development.…”

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confidence: 99%

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Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors

Zhang,

Tu,

Tao

et al. 2024

ACS Med. Chem. Lett.

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Developing selective CDK7 inhibitors has emerged as a promising approach for cancer treatment owing to the critical role of CDK7 in cancer progression. 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. The representative compound, 22, displayed significant enzymatic inhibitory activity and demonstrated a remarkable selectivity profile against a panel of kinases, including seven CDK subtypes. Modeling studies and molecular dynamics simulations revealed that the sulfone group of 22 significantly enhanced the binding affinity, while the acetyl group contributed to the increased selectivity of CDK7 against CDK9. 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.

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230MO First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies

Cited by 7 publications

References 0 publications

The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors

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