Phase I dose escalation study of the first-in-class selective PTEFb inhibitor BAY 1251152 in patients with advanced cancer: Novel target validation and early evidence of clinical activity.

Diamond, Jennifer R.; Moreno, Víctor; Lim, Emerson A.; Cai, Charles L.; Ince, Stuart; Lettieri, John; Merz, Claudia; Valencia, Ray; Boni, Valentina

doi:10.1200/jco.2018.36.15_suppl.2507

Cited by 12 publications

(12 citation statements)

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“…The discovery of VIP152, in optimizing atuveciclib, demonstrates promising translation of our efforts in early clinical studies . The improved selectivity on CDK9 starting from removal of the CDK2 activity, ATP independence, and a short-lived, iv strategy resulted in a promising 38% disease control rate in the first 31 patients in the dose escalation phase of VIP152’s first-in-human study.…”

Section: Discussionmentioning

confidence: 99%

Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer

et al. 2021

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Selective inhibition of exclusively transcription-regulating positive transcription elongation factor b/CDK9 is a promising new approach in cancer therapy. Starting from atuveciclib, the first selective CDK9 inhibitor to enter clinical development, lead optimization efforts aimed at identifying intravenously (iv) applicable CDK9 inhibitors with an improved therapeutic index led to the discovery of the highly potent and selective clinical candidate VIP152. The evaluation of various scaffold hops was instrumental in the identification of VIP152, which is characterized by the underexplored benzyl sulfoximine group. VIP152 exhibited the best preclinical overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats upon once weekly iv administration. VIP152 has entered clinical trials for the treatment of cancer with promising longterm, durable monotherapy activity in double-hit diffuse large B-cell lymphoma patients.

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Section: Discussionmentioning

confidence: 99%

Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer

et al. 2021

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“…Currently, BAY 1251152 undergoes phase I clinical evaluation with no final report yet. Initial pharmacodynamics data analysis shows dose-dependent reduction of MYC , PCNA , and MCL-1 levels, all being relevant for cancer cell survival [51]. Interestingly, OTX015 clinical trial performed in AML patients harboring a number of diverse driving mutations resulted in partial blast clearance and recovery of platelets.…”

Section: Discussionmentioning

confidence: 99%

Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia

et al. 2019

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Introduction The chromosomal rearrangements of the mixed-lineage leukemia gene MLL (KMT2A) have been extensively characterized as a potent oncogenic driver in leukemia. For its oncogenic function, most MLL-fusion proteins exploit the multienzyme super elongation complex leading to elevated expression of MLL target genes. High expression of MLL target genes overwrites the normal hematopoietic differentiation program, resulting in undifferentiated blasts characterized by the capacity to self-renew. Although extensive resources devoted to increased understanding of therapeutic targets to overcome de-differentiation in ALL/AML, the inter-dependencies of targets are still not well described. The majority of inhibitors potentially interfering with MLL-fusion protein driven transformation have been characterized in individual studies, which so far hindered their direct cross-comparison. Methods In our study, we characterized head-to-head clinical stage inhibitors for BET, DHODH, DOT1L as well as two novel inhibitors for CDK9 and the Menin-MLL interaction with a focus on differentiation induction. We profiled those inhibitors for global gene expression effects in a large cell line panel and examined cellular responses such as inhibition of proliferation, apoptosis induction, cell cycle arrest, surface marker expression, morphological phenotype changes, and phagocytosis as functional differentiation readout. We also verified the combination potential of those inhibitors on proliferation and differentiation level. Results Our analysis revealed significant differences in differentiation induction and in modulating MLL-fusion target gene expression. We observed Menin-MLL and DOT1L inhibitors act very specifically on MLL-fused leukemia cell lines, whereas inhibitors of BET, DHODH and P-TEFb have strong effects beyond MLL-fusions. Significant differentiation effects were detected for Menin-MLL, DOT1L, and DHODH inhibitors, whereas BET and CDK9 inhibitors primarily induced apoptosis in AML/ALL cancer models. For the first time, we explored combination potential of the abovementioned inhibitors with regards to overcoming the differentiation blockage. Conclusion Our findings show substantial diversity in the molecular activities of those inhibitors and provide valuable insights into the further developmental potential as single agents or in combinations in MLL-fused leukemia. Electronic supplementary material The online version of this article (10.1186/s13045-019-0749-y) contains supplementary material, which is available to authorized users.

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“…BAY1251152 demonstrated antitumor efficacy in AML xenograft models and progressed to phase I clinical evaluation ( 240 ). BAY1251152 was administered once weekly for 3 weeks as a 30 minute IV infusion to patients with metastatic solid cancers or aggressive non-Hodgkin lymphoma and caused the disease to stabilize in 12 out of 31 patients with a manageable safety profile (NCT02635672) ( 241 ). This compound is also currently under investigation in patients with advanced hematological malignancies (phase I, NCT02745743).…”

Section: Inhibitors Of Cdk9 As Therapeutic Agents For Cancermentioning

confidence: 99%

CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents

et al. 2021

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Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.

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Phase I dose escalation study of the first-in-class selective PTEFb inhibitor BAY 1251152 in patients with advanced cancer: Novel target validation and early evidence of clinical activity.

Cited by 12 publications

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Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer

Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer

Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia

CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents

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