Colorectal fibroblasts promote malignant phenotype of CRC cells by activating the ERK signaling pathway.

Based on a clinical staged small molecular hClpP activator ONC201, a class of novel hClpP agonists with a [1,8]naphthyridinone scaffold were designed, synthesized and evaluated in a series of biochemical and biological assays. Mechanism studies for the representative compound F20 indicated that it can potently bind to and activate hClpP, efficiently promote the degradation of hClpP substrates, robustly induce ATF4/CHOP regulated integrated stress responses, strongly inhibit cell growth and effectively induce apoptosis in a subset of cancer cell lines. F20 showed good PK profiles when dosed by intravenous injection and exhibited moderate oral bioavailability in mice.

P1/2, N=0, Withdrawn, M.D. Anderson Cancer Center | N=36 --> 0 | Initiation date: Jul 2024 --> Jan 2025 | Not yet recruiting --> Withdrawn

Imipridones are a promising strategy for further testing and development in mUM.

The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.

P1, N=20, Active, not recruiting, University of Nebraska | Trial primary completion date: Aug 2024 --> Oct 2026

P1/2, N=120, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Nov 2024 --> Nov 2026

Finally, we discovered that AIBP could control the MAPK signaling pathway-involved genes expression, including P-MEK, MEK, c-Myc, P-ERK1/2, and ERK1/2, and that GDC-0994, a specific ERK1/2 inhibitor, could suppress the AIBP overexpression induced cell migration and proliferation abilities. These findings demonstrated that the ERK/MAPK signaling pathway might be stimulated by AIBP in HCC tissues, leading to increased cell invasion, migration, and proliferation. It was hypothesized that AIBP might act as a useful prognostic and diagnostic marker for HCC.

The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.

Our results have relevance to activity of ONC201 in PCa where most castrate-resistant androgen-independent cancers are not therapy resistant due to NET differentiation. Importantly, NET differentiation does not promote resistance to ONC201 supporting further clinical investigations across the spectrum of PCa.

This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

P1/2, N=200, Active, not recruiting, Erasca, Inc. | Phase classification: P1b/2 --> P1/2 | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: May 2024 --> May 2025

Based on the founding member of imipridones, ONC201, a class of dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in a series of biochemical and biological assays as human caseinolytic protease P (hClpP) activators...More importantly, XT6 exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier. It showed highly potent in vivo antitumor activity in a MIAPACA2 cell line derived pancreatic cancer model in BALB/c nude mice.

P2, N=27, Not yet recruiting, University of Nebraska | Phase classification: P1 --> P2

Our results indicate that in this study NE3107 was associated with what appear to be positive neurophysiological and neuropsychological findings, as well as evidence of improvement in biomarkers associated with neuroinflammation and AD in patients diagnosed with dementia. Our findings are consistent with previous preclinical and clinical observations and highlight a central role of neuroinflammation in AD pathogenesis.

P1, N=10, Terminated, Shanghai Hengrui Pharmaceutical Co., Ltd. | N=105 --> 10 | Trial completion date: Aug 2023 --> May 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2023 --> May 2024; R&d strategy adjustment

P2, N=5, Recruiting, Neurological Associates of West Los Angeles | Not yet recruiting --> Recruiting | Phase classification: P2a --> P2 | Trial completion date: Jul 2024 --> Jul 2025 | Initiation date: Aug 2023 --> Dec 2023 | Trial primary completion date: Jun 2024 --> Dec 2024

NRF3, a tumor suppressor downregulated by VCP, could attenuate cell metastasis in TNBC cells by increasing cellular ROS accumulation and subsequently inhibiting the ERK phosphorylation.

P1, N=58, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Jan 2025 --> Jul 2025

P1, N=27, Not yet recruiting, University of Nebraska | Initiation date: Apr 2024 --> Jul 2024

P1/2, N=17, Terminated, Chimerix | Active, not recruiting --> Terminated; This study was terminated due to a change in corporate priorities. The decision to terminate the study was not based on any safety concerns.

Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.

DNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201.

The imipridones ONC201 and ONC206 induce mitochondrial dysfunction and have emerged as promising therapies for DMG patients. Clinical translation of our studies has the potential to enable precision metabolic therapy and imaging for DMG patients. Imipridones induce GABA accumulation in diffuse midline gliomas, an effect that can be leveraged for therapy and non-invasive imaging.

Domperidone-induced reactive oxygen species (ROS) generation and N-acetylcysteine treatment mitigated ROS levels and restored cell viability. An in vivo xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.

Here, we applied the principles of computer-aided drug discovery to identify a novel low-molecular-weight compound, TLR inhibitory compound 10 (TIC10), and its potent derivative (TIC10g), which demonstrated dual inhibition of TLR7 and TLR9 signaling pathways...Western blot analysis revealed that TIC10g downregulated the phosphorylation of the p65 subunit of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase, p38-MAPK, and c-Jun N-terminal kinase. These findings indicate that the novel ligand, TIC10g, is a specific dual inhibitor of endosomal TLRs (TLR7 and TLR9), disrupting MAPK- and NF-κB-mediated proinflammatory gene expression.

The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients.

P2, N=360, Recruiting, University of California, San Francisco | Phase classification: P1/2 --> P2

The mechanism of impairment of ONC201/206/212 effect caused by dopamine pre-treatment appears to involve upregulation of anti-apoptotic p-Bad, XIAP, FLIP and pAkt. Our results shed light on mechanisms of cancer cell protection by dopamine after imipridone treatment, heterogeneity among different tumor cell types, and suggest that effects of dopamine adaptation on tumor cells may impact on cell survival pathways in ways that may or may not depend on expression of dopamine receptors.

P1/2, N=360, Recruiting, University of California, San Francisco | Phase classification: P2 --> P1/2 | Trial completion date: Jun 2027 --> Jun 2029

Sorafenib showed improved anti-tumor effects when co-treated with SCH772984, an extracellular signal-regulated kinase inhibitor. Our study suggests new therapeutic strategies for canine HCC, and these cell lines are valuable research materials for understanding HCC tumor biology in both humans and dogs.

The pharmacological activation of ClpP using TIC10, currently in phase III clinical trials for cancer, successfully replicates this phenotype both in vitro and in vivo and markedly reduces aneurysm development in a mouse model of elastase-induced aortic aneurysms. Our mechanistic exploration indicates that ClpP activation regulates the VSMC phenotype by modifying the cellular NAD+/NADH ratio and activating Sirtuin 1. Our findings reveal the crucial role of mitochondrial proteostasis in the regulation of the VSMC phenotype and propose the ClpP protease as a novel, actionable target for manipulating the VSMC phenotype.

The IHC of the excised tumor grafts further confirmed the higher apoptosis and lower metastasis and cell proliferation. Thus, our MUC1 targeting binary drug-releasing liposomal formulation showed higher drug payload, enhanced plasma stability, and accumulation of drugs in the pancreatic orthotopic tumor and thus is a promising therapeutic alternative for the treatment of PDAC.

ERK activation, SIRT1/PGC-1α-axis, and TP4-induced apoptosis were all significantly reversed by the ERK inhibitor SCH772984. Finally, the inhibitory effect of TP4 on tumor growth has been confirmed in a zebrafish bladder cancer xenotransplantation model. These findings suggest that TP4 may be a potential agents for human bladder cancer through apoptosis induction, ERK activation, and the promotion of SIRT1-mediated signaling pathways.

Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.

P2, N=324, Recruiting, University of California, San Francisco | Active, not recruiting --> Recruiting | N=143 --> 324

Further in vitro, in vivo, and clinical studies are needed to explore their potential in cancer treatment. The online version contains supplementary material available at 10.1007/s40203-024-00213-4.

Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS.

ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition.

Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

P1, N=50, Recruiting, Nader Sanai | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=27, Not yet recruiting, University of Nebraska | Trial completion date: Jan 2027 --> Apr 2027 | Initiation date: Jan 2024 --> Apr 2024 | Trial primary completion date: Jan 2026 --> Apr 2026