P1, N=14, Active, not recruiting, Novartis Pharmaceuticals | Phase classification: P1/2 --> P1

Patients with STK11-mutant NSCLC had low PD-L1 expression and ORR to ICIs, and their PFS and OS were worse than patients with STK11wt after comprehensive treatment. In the future, more reasonable systematic treatments should be explored for this subgroup of patients with STK11-mutant NSCLC.

Our study provides a comprehensive understanding of the biological role of CLDN18-based bioinformatics and machine learning analysis in STAD, shedding light on its prognostic significance and potential therapeutic implications. To fully elucidate the molecular intricacies of CLDN18, further investigation is warranted, particularly through in vitro and in vivo studies.

P1, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Phase classification: P1b --> P1

Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-xL/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. We demonstrate a preferential engagement of cell death over G1 cell cycle arrest, mechanistically implicating MCL-1-binding pro-apoptotic sensitizer NOXA. The proposed combination of two clinical-stage compounds independently under clinical evaluation for ALL is of high clinical relevance and warrants consideration for the treatment of patients with high-risk and relapsed ALL.

P1/2, N=58, Recruiting, Centre Leon Berard | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

Furthermore, the on-target activities of 2 were general and applicable to other cancer cell lines with wild type p53. These attributes make 2 a good candidate for future optimization to discover a potential treatment of wild-type p53 cancer.

P1/2, N=38, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | N=183 --> 38

In this work, we compared the properties of a drug-resistant cell line obtained during long-term cultivation in the presence of an Mdm2 inhibitor, Nutlin-3a, with a similarly obtained line insensitive to the cytostatic drug paclitaxel. While both targeted and general defense mechanisms are activated by the Mdm2 inhibitor, it still increases the susceptibility of tumor cells to other drugs. The results obtained indicate that the risks of developing chemoresistance under the therapy with a targeted agent are fundamentally lower than during cytotoxic therapy.

P1, N=0, Withdrawn, St. Jude Children's Research Hospital | N=52 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=70, Terminated, Kartos Therapeutics, Inc. | Phase classification: P1b/2 --> P1/2 | Trial completion date: Jul 2024 --> Sep 2023 | Active, not recruiting --> Terminated; In September 2023, the study was terminated because of a Sponsor decision, unrelated to safety concerns.

P1/2, N=0, Withdrawn, Kartos Therapeutics, Inc. | Phase classification: P1b/2 --> P1/2 | N=92 --> 0 | Trial completion date: Dec 2027 --> Jun 2027 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2025 --> Jun 2025

All samples were processed for histopathological analysis (HE, IHC and DNAscope™), Western blot, and qPCR; moreover, 3D collagen-based models were treated with different doses of SAR405838, a well-known inhibitor of MDM2, and cell viability was assessed in comparison to 2D model drug response...3D collagen samples showed higher cell viability after SAR40538 treatment than 2D models, while cells sensitive to the drug died by apoptosis or necrosis. Our results prompt us to extend our investigation by applying our 3D models to further oncological relevant applications, which may help address unresolved questions about dedifferentiated liposarcoma biology.

Analysis of five trajectories, including RMSD, RMSF, hydrogen bond, radius of gyration, coulomb short-range electrostatic spectra, and free binding energy, confirmed that Mol-126 exhibited the highest structural stability compared to the reference drug (Alrizomadlin). Notably, Mol-126 is a derivative of 3-phenoxypropionic acid, which shows promise for the development of alternative therapeutic treatments for non-responsive bladder cancer patients.Communicated by Ramaswamy H. Sarma.

P1/2, N=14, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2026 --> May 2024 | Trial primary completion date: May 2025 --> May 2024

In this study, using mass spectrometry and Western blotting, we detected expression of DRAXIN in a medium of A549 cells exposed to A + N. Thus, this protein functions not only in the development of the nervous system, but it may also have a new cancer-related function.

P1, N=38, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Feb 2025 | Trial primary completion date: Dec 2023 --> Aug 2023

Consistently, pharmacological activation of p53 using nutlin-3 or doxorubicin reduced FOXQ1 mRNA and protein levels in cancer cell lines harboring wild-type p53. Finally, we observed that p53 mutations are associated with increased FOXQ1 expression in human cancers. Altogether, these results suggest that loss of p53 function - a hallmark feature of many types of cancer - de-represses FOXQ1, which in turn promotes tumour progression.

P1/2, N=34, Suspended, University of Michigan Rogel Cancer Center | Recruiting --> Suspended

P1/2, N=69, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=224, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=8, Terminated, Novartis Pharmaceuticals | N=38 --> 8 | Trial completion date: Jan 2028 --> Oct 2023 | Recruiting --> Terminated | Trial primary completion date: Jan 2027 --> Oct 2023; Study has been stopped following to strategic decision from the Sponsor. Not based on any safety findings or safety concerns with siremadlin.

P1/2, N=14, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors.

Although two MDM2-recruiting heterobifunctional molecules reduced HDAC1 and HDAC2 abundance with complete selectivity over HDAC3 and reduced HDAC1/2 corepressor components LSD1 and SIN3A, we were surprised to observe that idasanutlin alone was also capable of this effect. This finding suggests an association between the MDM2 E3 ligase and HDAC1/2 corepressor complexes, which could be important for designing future dual/bifunctional HDAC- and MDM2-targeting therapeutics, such as PROTACs.

This study provides a new effective and low-toxicity drug candidate from licochalcone derivatives for treating cervical cancer.

P1, N=24, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1

Through its influence on TP53 mutation, MRPL21 promotes HCC proliferation and progression while conferring resistance to apoptosis. These findings suggest that MRPL21 holds promise as a valuable biomarker for the treatment of HCC.

P1, N=58, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=86, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=40, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=52, Not yet recruiting, St. Jude Children's Research Hospital

High-risk patients were more sensitive to some small molecules compounds like camptothecin_1003, cisplatin_1005, cytarabine_1006, nutlin-3a (-)_1047, gemcitabine_1190, WZ4003_1614, selumetinib_1736 and mitoxantrone_1810. In summary, our study comprehensively explored the role of NETosis-related genes in gastric cancer, which can provide direction for relevant studies.

P2, N=1, Terminated, Institut Curie | N=48 --> 1 | Trial completion date: Dec 2026 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2025 --> Nov 2023; Financial partner providing study drug could no longer support the trial

These results indicate the potential of nutlin-3a as an alternative agent for treating KRAS mutant/p53 wild type NSCLC cells.

More importantly, (-)60 exhibited good PK properties and exerted robust antitumor efficacies in a systemic mouse xenograft model of MOLM-13. Taken together, our study showcases a class of potent MDM2 inhibitors featuring a novel spiro-indoline scaffold, which is promising for future development targeting cancer cells with wild-type p53.

Other tested covariates, including body weight, creatinine clearance, aspartate transaminase, alanine transaminase, bilirubin, albumin, alpha 1-acid glycoprotein, race, UGT1A1 genotype, recent ruxolitinib treatment in MF, and CYP3A4 inducer/inhibitor concomitant medications, were not significant. Tumor type influenced navtemadlin exposure with simulated exposure in R/R MF patients at the selected Phase 3 dose of 240 mg comparable to exposures in MCC patients at 180 mg, the selected Phase 2 dose for that indication. Cancer-associated inflammation and/or treatment history, as well as age and female sex, may increase navtemadlin exposure. The PD marker MIC-1 responds to navtemadlin in a concentration-dependent fashion.

Combination treatment with idasanutlin and navitoclax, a potent Bcl-2/Bcl-xL inhibitor, induces more consistent and potent synergistic killing of T-ALL PDX lines in vitro than venetoclax, a Bcl-2 specific inhibitor. Moreover, a marked synergic response to combination treatment with idasanutlin and navitoclax was seen in vivo in all four T-ALL xenografts tested, with a significant increase in overall survival in the combination treatment group. Collectively, these preclinical data show that the combination of idasanutlin and navitoclax is highly active in T-ALL and may merit consideration in the clinical setting.

MD simulation revealed a median potency in comparison with Nutlin-3a...We attempted to use Monastrol scaffold as a potent inhibitor of MDM2 rather than an Eg5 inhibitor using in silico modification. The results obtained from the in silico and in vitro evaluations were noteworthy and warranted much more effort in the future.

P2, N=36, Recruiting, Ascentage Pharma Group Inc. | Phase classification: P2a --> P2 | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2023 --> May 2024

P1, N=52, Not yet recruiting, St. Jude Children's Research Hospital | Phase classification: P1b --> P1

P2, N=48, Active, not recruiting, Institut Curie | Recruiting --> Active, not recruiting