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Resistance to targeted therapies is a major challenge in oncology. Disease progression is caused by multiple resistance mechanisms. Besides pre-existing and acquired genetic alternations, adaptive non-mutational reprogramming as well as modulation of phenotypic plasticity have emerged as drivers of disease progression. For example, in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients who were treated with osimertinib, ~50% of progressive disease could not be attributed to genetic mutations (Leonetti et al., BJC 2019). Similarly, in ~ 40% of patients suffering from KRAS G12C-mutated NSCLC and colorectal cancer (CRC), disease progressed under sotorasib treatment without identifiable acquired mutations (Zhao et al., Nature 2021). Thus, targeting non-genetic adaptive resistance mechanism such as drug-induced transcriptional reprogramming might be of great therapeutic benefit. Here we identified small molecules, that interfere with cancer drug-induced transcriptional escape mechanisms using a phenotypic screen based on an SRY-Box Transcription Factor 2 (SOX2) reporter system. The screen led to the development of TT125-802, a highly specific and potent, orally available small molecule inhibitor of the bromodomain of the transcriptional and epigenetic regulator CBP [cyclic adenosine monophosphate response element binding protein (CREB) binding protein] and its paralogue p300. TT125-802 dose-dependently prevented osimertinib resistance development in EGFR-mutated NSCLC cell lines HCC827 and HCC4006, as well as sotorasib resistance development in KRAS G12C-mutated NCI-H358 (NSCLC), SW837 and SNU-1411 (CRCs) as assessed by label-free long-term live microscopy assays. Data generated in mouse xenograft studies confirmed the ability of TT125-802 increasing response rates and prolonging the duration of response to osimertinib and sotorasib in vivo. In cells and tumours which were already resistant to osimertinib or sotorasib, TT125-802 could still delay cell or tumor growth. Complementary and longitudinal analysis of transcriptional changes using RNA sequencing in vitro and in vivo identified several early adaptive and late acquired resistance signatures that were reversed by TT125-802. A first-in-human study of TT125-802 in cancer patients is on track to start in 2023. Citation Format: Thomas Bohnacker, Dorothea Gruber, Sara Laudato, Martin Schwill, Charles-Henry Fabritius, Raquel Herrador, Katrin Westritschnig, Thushara Pattupara, Vikram Ayinampudi, Stefanie Flückiger-Mangual. Targeting adaptive resistance to EGFR and KRAS G12C inhibitors by TT125-802, a novel and specific CBP/p300 bromodomain inhibitor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3907.

Maternal embryonic leucine zipper kinase (MELK) is involved in several key cellular processes and displays increased levels of expression in numerous cancer classes (colon, breast, brain, ovary, prostate and lung). Although no selective MELK inhibitors have yet been approved, increasing evidence suggest that inhibition of MELK would constitute a promising approach for cancer therapy. A weak high-throughput screening hit (17, IC50 ≈ 5 μM) with lead-like properties was optimized for MELK inhibition. The early identification of a plausible binding mode by molecular modeling offered guidance in the choice of modifications towards compound 52 which displayed a 98 nM IC50. A good selectivity profile was achieved for a representative member of the series (29) in a 486 protein kinase panel. Future elaboration of 52 has the potential to deliver compounds for further development with chemotherapeutic aims.

The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels – TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.

The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Aberrant activation by a wide range of exogenous and endogenous signals can lead to chronic, low-grade inflammation. It has attracted a great deal of interest as a drug target due to the association with diseases of large unmet medical need such as Alzheimer's disease, Parkinson's disease, arthritis, and cancer. To date, no drugs specifically targeting inhibition of the NLRP3 inflammasome have been approved. In this work, we used the known NLRP3 inflammasome inhibitor CP-456,773 (aka CRID3 or MCC 950) as our starting point and undertook a Structure-Activity Relationship (SAR) analysis and subsequent scaffold-hopping exercise. This resulted in the rational design of a series of novel ester-substituted urea compounds that are highly potent and selective NLRP3 inflammasome inhibitors, as exemplified by compounds 44 and 45. It is hypothesized that the ester moiety acts as a highly permeable delivery vehicle and is subsequently hydrolyzed to the carboxylic acid active species by carboxylesterase enzymes. These molecules are greatly differentiated from the state-of-the-art and offer potential in the treatment of NLRP3-driven diseases, particularly where tissue penetration is required.

A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT6 receptor (5-HT6R) was synthesized and characterized. The series was optimized to reduce activity on D2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice. Compound 3, the demethylated version of compound 1c, was profiled against a panel of 106 receptors, channels and transporters, indicating only D3 receptor as a major off-target. Compound 3 has been selected for this study over compound 1c because of the higher 5-HT6R/D2R binding ratio. These results have defined a new direction for the design of our pseudo-selective 5-HT6R antagonists.

In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation.

A stereoselective approach to the 8b-azaacenaphthylene ring system is described. This new route features a dichloroketene-enol ether [2 + 2] cycloaddition, a vinylogous Mannich reaction, and an aza-Prins cyclization as key stereoselective transformations.

MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development and progression of solid tumors and hematological malignancies has been widely discussed, particularly in the context of cap dependent translation, regulated by phosphorylation of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic, cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL, SMAD2, β-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation. MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor effects observed in genetic knockout and RNA interference experiments and at the same time lack of adverse effects in dual knockout animals. There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not only tools for further basic research studies but also potential drugs in diseases characterized by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive due to the absence of potent and selective probes. Moreover, in many instances, hypotheses have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently running at the preclinical stage. This review aims to provide an overview of recent progress in the development of MNK inhibitors.

Herewith, we report development of small molecule inhibitors of MNK1 and MNK2 kinases and their cellular activity. MNK1 and 2 are MAP kinase-interacting kinases are activated by RAS and MAPK signaling pathways, and are involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4e on a conserved serine 209. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in diverse types of cancer. Interestingly, mice that lack both Mnk1 and Mnk2 do not have any apparent phenotype. Recently first dual MNK1/MNK2 inhibitors have entered clinical trials as a combinational therapy with docetaxel in NSCLC. SEL201 is a series of small molecule inhibitors which inhibit activity of both MNK1 and MNK2 in a low nM range and high selectivity confirmed in kinome panels. Analysis of SEL201 cellular activity indicated potent inhibition of eIF4e Ser209 in vitro in cancer cells and in vivo after oral administration in xenograft tumors. Repressed phosphorylation of eIF4e resulted in impaired translation of several proteins involved in metastasis and activation of immune cells. High potency, selectivity and favorable ADME/PK profile indicates that SEL201 inhibitors would be useful tools in probing molecular consequences of eIF4e Ser209 inhibition in cancer cells. SEL201 in vitro and in vivo activities on viability and metastasis will be presented in cellular and in vivo models of solid tumors and hematological malignancies. SEL201 series is further developed as a cancer therapy with a good therapeutic window. Citation Format: Tomasz Rzymski, Agnieszka Dreas, Ewelina Wincza, Charles-Henry Fabritius, Urszula Kulesza, Katarzyna Kucwaj- Brysz, Mariusz Milik, Aniela Gołas, Renata Windak, Eliza Żyłkiewicz, Anna Wróbel, Maciej Sułkowski, Krzysztof Brzózka. Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C194.

The isolation of a stable beta-hydrogen-containing R-PdLn-X complex (R = alkyl; X = halide) issued from a Heck reaction is reported together with some aspects of its reactivity.

The isolation of a stable β-hydrogen-containing R-PdLn-X complex (R = alkyl; X = halide) issued from a Heck reaction is reported together with some aspects of its reactivity.