roniciclib (BAY1000394) / Bayer - LARVOL DELTA

Computational Estimation of Residence Time on Roniciclib and Its Derivatives against CDK2: Extending the Use of Classical and Enhanced Molecular Dynamics Simulations. (PubMed, ACS Omega) - "Furthermore, our analysis of protein flexibility at the C-terminus and N-terminus angles revealed a relationship with the size of the R5 substituent in the bound inhibitor, supported by principal component analysis. Additionally, different unbinding pathways were proposed, where it was found that inhibitors can dissociate from the CDK2 binding site through two principal routes: the α-helix D and β-1 and β-2 segments."

Journal • CDK2

Target identification, selectivity profiling and binding site mapping of small molecule and peptide drugs by LiP-MS (AACR 2024) - "In this study, we present target deconvolution results on four small molecule compounds and one peptide compound with very distinct pharmacological profile: 1) staurosporine, a broad-specific kinase inhibitor; 2) roniciclib, a failed clinical-stage pan-CDK inhibitor; 3) selumetinib, an allosteric, non-ATP-competitive MEK 1 and 2 inhibitor; 4) NST-628, a newly developed non-degradating molecular glue inhibiting the RAS/MAPK pathway; and 5) Acetyl-calpastatin, a 24 amino-acid polypeptide inhibitor of calpain 1 and 2. Nature Comm 2020 [2] Hendricks and Beaton et al. ACS Chem Bio 2021 [3] AACR 2022 [4] AACR 2023 [5] AACR-NCI-EORTC 2023"

Oncology • CAPN1 • CDK1 • CDK2 • CDK4 • CDK9 • MAP2K1 • MAP2K2

An Overview of CDK Enzyme Inhibitors in Cancer Therapy. (PubMed, Curr Cancer Drug Targets) - "We have mentioned first-generation pan-CDKIs, flavopiridol and roscovitine, as well as second-generation CDKIs, dinaciclib, P276-00, AT7519, TG02, roniciclib, and RGB-286638, based on their research phases, clinical trials, and cancer targeting. CDKIs are CDK4/6, CDK7, CDK9, and CDK12 inhibitors. Finally, we have looked into the efficacy of CDK inhibitors and PD1/PDL1 antibodies when used together, which could lead to the development of a viable cancer treatment strategy."

Journal • Oncology • CDK4 • CDK7 • CDK9

An Overview of CDK3 in Cancer: Clinical Significance and Pharmacological Implications. (PubMed, Pharmacol Res) - "Further evaluation of this role has been hampered by the lack of selective pharmacological inhibitors. Herein, we provide a comprehensive overview about the therapeutic potential of targeting CDK3 in cancer."

Journal • Review • Eye Cancer • Oncology • Retinal Disorders • Retinoblastoma • Sarcoma • Solid Tumor • CDK2 • CDK4 • CDK6 • E2F1 • EGFR

CDK inhibitors in cancer therapy, an overview of recent development. (PubMed, Am J Cancer Res) - "We reviewed first-generation pan-CDKIs Flavopiridol and Roscovitine, and second-generation CDKIs Dinaciclib, P276-00, AT7519, TG02, Roniciclib, RGB-286638 by focusing on their developing stages, clinical trials and targeting cancers. These CDKIs include CDK4/6, CDK7, CDK9, and CDK12/13 inhibitors. Finally, the efficacy and discrepancy of combination therapy with CDK inhibitors and PD1/PDL1 antibodies were analyzed, which might give insights into the development of promising strategy for cancer treatment."

Journal • Review • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK12 • CDK7 • CDK9

[VIRTUAL] Increasing complexity: A practical synthetic approach to three dimensional, cyclic sulfoximines and first insights into their in vitro properties (ACS-Fall 2020) - "Nevertheless, four sulfoximine compounds (roniciclib, atuveciclib, BAY 1251152, AZD6738) have entered clinical evaluation of late and their promising physicochemical and DMPK properties were important triggers for their selection as clinical candidates.However, only limited literature on the synthesis of cyclic sulfoximines (3) and their properties is currently available. This presentation highlights a practical, safe approach for the synthesis of five- to seven-membered cyclic sulfoximines (3), which are currently underrepresented in drug discovery.To gain further knowledge of the medicinal chemistry properties of cyclic sulfoximines (3), the behavior of fragment-like reaction products 3 was evaluated in selected in vitro assays (aqueous solubility, metabolic stability, Caco2 permeability, logD) and compared to acyclic analogues (2). In order to overcome the limitations of analyzing such small and fragment-like compounds we also compared the in vitro properties of..."

Preclinical

Roniciclib down-regulates stemness and inhibits cell growth by inducing nucleolar stress in neuroblastoma. (PubMed, Sci Rep) - "Furthermore, we found that high expression of Nucleophosmin-1 correlates with patients' short survival. The co-expression of several stem cell surface antigens such as CD44v6 and CD114, together with the nucleolar markers here described, extends new possibilities to isolate undifferentiated subpopulations from neuroblastoma and identify new targets for the treatment of this childhood malignancy."

Journal • Neuroblastoma • Oncology • Solid Tumor • CD14 • CD44 • CSF3R • NPM1

Clinical Study to Evaluate the Maximum Tolerated Dose of BAY1000394 When Given Together With Chemotherapy and the Effectiveness of This Combination Treatment in Shrinking a Specific Type of Lung Tumors (Smal Cell Lung Cancer) (clinicaltrials.gov) - P1/2; N=42; Active, not recruiting; Sponsor: Bayer; Trial primary completion date: Jul 2016 ➔ Mar 2016

Trial primary completion date • Biosimilar • Oncology • Small Cell Lung Cancer

Clinical study to evaluate the maximum tolerated dose of BAY1000394 when given together with chemotherapy and the effectiveness of this combination treatment in shrinking a specific type of lung tumors (smal cell lung cancer) (clinicaltrials.gov) - P1/2, N=60; Not yet recruiting; New P1/2 trial

New indication • New trial • Pipeline shift • Oncology

Bayer: Meet Management in London (Bayer AG) - "Roniciclib (BAY 1000394) – pan-CDK Inhibitor Developed for SCLC"; "Promising Phase I clinical data"; "On average, patients with stable disease (SD) stayed on treatment for 103.5 days (4-9 cycles)"; "Disease control rates were 29% (n=9/31) for SCLC, 36% for OC (n=9/25), and 33.3% for patients harboring tumor-specific mutations (n=2/6)"; "Majority of AE’s were grade 1 or 2"

P1 data • Oncology

A dose-escalation phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 28 days on/14 days off schedule (ASCO 2012) - Presentation time: Monday June 4, 8:00 AM to 12:00 PM; P1, N=10; 14856; Drug-related grade 3 AEs were hyponatremia (2 pts) and edema, lymphopenia, myalgia, fatigue, and hypokalemia in 1 pt each; Hyponatremia in one and hypokalemia in another patient were dose limiting toxicities in cohort 2; Enrollment has been stopped; BAY 1000394 PK was dose proportional and T1/2 was 13 hours, major metabolite levels were low

P1 data • Oncology

Bayer: Meet Management in London (Bayer AG) - Anticipated completion of P2 trial for small cell lung cancer at the end of 2015; Anticipated presentation of P2 data for small cell lung cancer at ESMO (Oct 07-11, 2016)

Anticipated P2 data • Anticipated trial completion date • Oncology

Computing tumor growth rate across pre- and post-treatment periods uncovers anti-tumor activity in patients treated by a pan-CDK inhibitor (BAY1000394) (AACR 2014) - Presentation time: Sunday, Apr 06, 2014, 1:00 PM - 5:00 PM; Abstract #900; P=1, N=12; NCT01335256; "At the time of first evaluation, 9 patients were classified as progressive disease (PD) and 3 as stable disease (SD) using RECIST. Conversely, TGR decreased in 6 out of 12 patients (median: - 9.8 %; CI 95% - 27.4 to 2.3), suggesting antitumor activity by the investigational drug...two patients suffering from ovary adenocarcinoma with durable SD (10 treatment cycles) had almost no tumor growth rate change between the REFERENCE and the EXPERIMENTAL period, suggesting no anti-tumor activity, and could potentially have been discontinued earlier from the trial."

P1 data • Oncology

Bayer: Roadshow Paris (Bayer AG) - Anticipated completion of P2 CONCEPT-SCLC trial (NCT02161419) in small cell lung cancer in H1 2016

Anticipated trial completion date • Oncology

CONCEPT-SCLC: RONICICLIB / Placebo in Combination With Chemotherapy in Small Cell Lung Cancer (clinicaltrials.gov) - P2; N=142; Terminated; Sponsor: Bayer; N=79 ➔ 142

Enrollment change • Biosimilar • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 3 days on/4 days off schedule (ASCO 2012) - Presentation time: Saturday June 2, 1:15 PM to 5:15 PM; P1, N=34; 14484; DLTs (grade 3, 1 pt each) were hyponatremia, aphtous stomatitis at 19.2 mg solution and arterial thrombosis at 15 mg tablet; SD lasting for 2-4 months was observed in 9 patients, among others in 4 of 4 mesothelioma and 2 of 2 ovarian pts; One additional pt with cholangiocarcinoma has ongoing SD lasting for 5 months; One of the ovarian pts had a significant decline of CA125 lasting for 3 months

P1 data • Oncology

Phase II Study of Roniciclib in Combination with Cisplatin/Etoposide or Carboplatin/Etoposide as First-Line Therapy in Patients with Extensive-Disease Small-Cell Lung Cancer. (PubMed, J Thorac Oncol) - "Roniciclib combined with chemotherapy demonstrated an unfavorable risk-benefit profile in patients with ED-SCLC and the study was prematurely terminated."

Clinical • Combination therapy • Journal • P2 data • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer

Phase Ib/II study of the pan-cyclin-dependent kinase inhibitor roniciclib in combination with chemotherapy in patients with extensive-disease small-cell lung cancer. (PubMed, Lung Cancer) - "Roniciclib co-administered with chemotherapy in patients with ED-SCLC demonstrated tolerability, acceptable pharmacokinetics, and promising efficacy. An observed safety signal in a related phase II study resulted in discontinuation of the present study and termination of further roniciclib development."

Clinical • Combination therapy • Journal • P1/2 data

Potent effects of roniciclib alone and with sorafenib against well-differentiated thyroid cancer. (PubMed, Endocr Relat Cancer) - "Acceptable safety profiles appeared in animals treated with either roniciclib alone or roniciclib and sorafenib combination therapy. These findings support roniciclib as a potential drug for the treatment of patients with well-differentiated thyroid cancer."

Journal

"No benefit of Roniciclib #cdk inhibitor in extensive #sclc #lungcancer ⁦@JTOonline⁩" (@MwAphp)