Publication in Pathology and Oncology Research journal on Combination of Farnesyl-Transferase Inhibition with KRAS G12D Targeting in Breaking Down Therapeutic Resistance in Pancreatic Cancer

10/12/2024 Publications Publication in Pathology and Oncology Research journal on Combination of Farnesyl-Transferase Inhibition with KRAS G12D Targeting in Breaking Down Therapeutic Resistance in Pancreatic Cancer KINETO Lab announcing that research about combination of farnesyl-transferase inhibition with KRAS G12D targeting brake down therapeutic resistance in pancreatic cancer, was published in Pathology and Oncology Research journal. Pancreatic adenocarcinoma is one of the deadliest forms of cancer with no effective therapeutic options. A KRAS mutation can be found in up to 90% of all pancreatic tumors, making it a promising therapeutic target. The introduction of new KRAS inhibitors has been a milestone in the history of KRAS mutant tumors; however, therapeutic resistance limits their efficacy. Thus, new therapeutic options, including combination therapies, are urgently needed. Recently, our collaborators and we have shown that KRAS G12C inhibitors in combination with farnesyl-transferase inhibitors exert synergistic antitumor effects. Here, we provide evidence for the feasibility of this combinational approach to break down resistance in KRAS G12D mutant pancreatic cancer. Although we have shown that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present in both 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance to MRTX1133 in 2D. The effects of the combination treatment show an association with the inhibition of farnesylated regulatory proteins, including HRAS and RHEB, along with the expression level of KRAS. This study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyl-transferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma. The publication can be accessed under the following link. Previous

Published a study about In Vitro and In Vivo Evaluation of Bombesin-MMAE Conjugates for Targeted Tumour Therapy, in European Journal of Medicinal Chemistry

12/11/2024 Publications Published a study about In Vitro and In Vivo Evaluation of Bombesin-MMAE Conjugates for Targeted Tumour Therapy, in European Journal of Medicinal Chemistry KINETO Lab announcing that research about in vitro and in vivo evaluation of bombesin-MMAE conjugates for targeted tumour therapy, was published in European Journal of Medicinal Chemistry. Prostate cancer is the most incident in male population and the second cause of death. Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. One of the target which can be exploited for targeted delivery of drugs is bombesin receptor 2 (BB2) which is highly overexpressed in prostate tumors. Therefore, our partners form HUN-REN-ELTE research group of Peptide Chemistry synthesized peptide drug conjugates (PDCs) containing bombesin receptor-targeting moiety which were armed with tubulin binder monomethyl auristatin E (MMAE), and with different in mouse plasma stability initial and optimized linkers. These PDCs were tested in vitro, as well as in in vivo experiments using both acute and chronic treatment strategies. All conjugates significantly inhibited the growth of a human prostate PC-3 tumor in mice in both acute and chronic in vivo efficacy studies compared to the control as well as to free drug groups. Moreover, in acute in vivo efficacy study all conjugates significantly extended survival of mice bearing PC-3 tumor, compared to the administration of the free drug and to the control group. One of the conjugate revealed good accumulation in tumor tissue in biodistribution studies, and showed outstanding antitumor effect and prolonged survival of mice, suggesting it possible application as targeted therapy against prostate cancer. The publication can be accessed under the following link. PreviousNext

Publication in Communications Chemistry journal on Mapping Protein Binding Sites by Photoreactive Fragment Pharmacophores

06/08/2024 Publications Publication in Communications Chemistry journal on Mapping Protein Binding Sites by Photoreactive Fragment Pharmacophores KINETO Lab announcing that research about mapping protein binding sites by photoreactive fragment pharmacophores, was published in Communications Chemistry journal. Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here is introduced a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of screening protocol was further improved by a target-conjugated photocatalyst. In collaboration with our partners there were designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRas-G12D protein, and the yet unliganded N-terminal domain of the STAT5B transcription factor. We have discovered several fragment hits against all three targets and identified their binding sites via enzymatic digestion, structural studies and modeling. The results revealed that this protocol outperforms screening traditional fully functionalized and photoaffinity fragments in better exploration of the available binding sites and higher hit rates observed for even difficult targets. The publication can be accessed under the following link. PreviousNext

Published a study about a gluing docking method for finding small molecules that bind to both the GAP and the mutated KRAS molecules

07/03/2024 Publications Published a study about a gluing docking method for finding small molecules that bind to both the GAP and the mutated KRAS molecules KINETO Lab proudly announcing that research in the frame of KRAS consortium about new approach for finding small molecules that can be used to attach GAP molecules to RAS proteins mutations to cure the most hard-to-treat cancers, was published in the International Journal of Molecular Sciences. A significant number of cancers in humans are related to changes in the genetic material, i.e. DNA mutations. More than 600 cancer-causing mutations are currently known. The most important of these are mutations of the RAS protein, which are found in 30% of all human tumors. The most difficult-to-treat human carcinomas such as adenocarcinomas of pancreas, colon and the lung, can be linked to them. Mutations in RAS prevent the GAP protein from binding to the RAS molecule, thereby allowing unrestricted cell division, thus the disease. Therefore, specific molecules are needed to glue the RAS and GAP molecules together, and restore normal fuction of RAS. KINETO Lab developed this strategy in the frame of KRAS consortium with partners. The preliminary results show that the best two small “glue” molecules found based on the new method compete with the best similar molecules found so far in the world, targeting KRAS-G12D mutation. The continuation of this work, may lead to find new drugs that are effective against the deadliest cancers and have few side effects, since the method does not interfere with the basic mechanisms of cell division, as is the case with chemotherapy interventions today, but instead restores the physiologically normal healthy state. The publication can be accessed under the following link. Previous

Published a new study on targeting KRAS with combination of KRAS-G12C and Farnesyl-transferase inhibitors in British Journal of Cancer

10/02/2024 Publications Published a new study on targeting KRAS with combination of KRAS-G12C and Farnesyl-transferase inhibitors in British Journal of Cancer We proudly announce that it is publiched the research of KINETO Lab and collaborators on targeting KRAS with combination of KRAS-G12C and Farnesyl-transferase inhibitors, in British Journal of Cancer. Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors. De novo and acquired resistance limit the efficacy of approved KRAS-G12C inhibitors for the treatment of KRAS-G12C mutant lung cancer. However, several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and in subcutaneous xenograft models of lung adenocarcinoma. Combination of tipifarnib with sotorasib shows synergistic inhibitory effects on lung adenocarcinoma cells in vitro in 2D and 3D. Mechanistically, we present antiproliferative effect of the combination and interference with compensatory HRAS activation and RHEB and lamin farnesylation. Enhanced efficacy of sotorasib in combination with tipifarnib is recapitulated in the subcutaneous xenograft model of lung adenocarcinoma. Finally, combination of additional KRAS-G12C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal and pancreatic adenocarcinoma cellular models. The publication can be accessed under the following link. Previous

Announce of the first publication using our Patient-Derived Tumor Xenograft (PDTX) models in Cells journal

27/07/2023 Publications Announce of the first publication using our Patient-Derived Tumor Xenograft (PDTX) models in Cells journal We are pleased to announce that the first paper related to study of our Patient-Derived Tumor Xenograft (PDTX) models, entitled „Evolving Acquired Vemurafenib Resistance in a BRAF V600E Mutant Melanoma PDTX Model to Reveal New Potential Targets” is now published in the journal Cells. In this research, our PDTX melanoma model was used to model acquired vemurafenib resistance in a BRAF V600E mutant genetic background. KINETO Lab’s model was able to identify novel expressional changes that drive therapy failure thus might be targeted to improve the efficacy. The publication can be accessed under the following link. PreviousNext

Publication in Frontiers in Pharmacology on Optimizing the Enzymatic Release of MMAE from isoDGR-based SMDC by Incorporation of a GPLG-PABC Enzymatically Cleavable Linker

13/07/2023 Publications Publication in Frontiers in Pharmacology on Optimizing the Enzymatic Release of MMAE from isoDGR-based SMDC by Incorporation of a GPLG-PABC Enzymatically Cleavable Linker As a member of Magicbullet::Reloaded Consortium, KINETO Lab took a big part in the study where the use of GPLG-PABC linker in a Small Molecule Drug Conjugates (SMDC), as an efficient lysosomal cleavable linker, is reported for the first time and, in the future, it might represent an alternative to other well-established enzymatically sensitive peptide sequences. Moreover, the antiproliferative activity of conjugate, in so called “kiss-and-run” protocol, resulted to be significantly more potent than the free MMAE, with the relative potency clearly consistent with the expression of the integrin receptor in the four cancer cell lines. The publication can be accessed under the following link. PreviousNext

Published a study about Activation-Free Sulfonyl Fluoride Probes for Fragment Screening

30/03/2023 Publications Published a study about Activation-Free Sulfonyl Fluoride Probes for Fragment Screening In Molecules journal was published the research about synthesis and characterization of a small sulfonyl fluoride library for tagging tractable targets at nucleophilic residues. Based on the results, it was propose that coupling diverse fragments to this warhead would result in a library of sulfonyl fluoride bits (SuFBits), available for screening against protein targets. After in-depth characterization at the surrogate level, SuFBits was successfully applied in labelling of the KRasG12D oncogene mutant, where also was confirmed the functional consequences of the covalent binding. The study was performed by KINETO Lab and collaborative labs in the frame of KRAS Consortium. The publication can be accessed under the following link. PreviousNext

Publication in European Journal of Medicinal Chemistry on covalent fragment mapping of KRasG12C which reveals novel chemotypes with in vivo potency

20/02/2023 Publications Publication in European Journal of Medicinal Chemistry on covalent fragment mapping of KRasG12C which reveals novel chemotypes with in vivo potency As a member of KRAS Consortium, KINETO Lab was big part of the research to identify fragments as suitable starting points targeting KRasG12C, pre-selected in covalent fragment screening of the electrophilic fragment library. Two hits, CFL-120 and CFL-137, confirming their cellular activity against a number of homozygous and heterozygous KRasG12C tumor cells, in comparison to wild type Kras cancerous and non-cancerous cells, were finally tested in vivo using a mouse xenograft model of human lung carcinoma. The fragments demonstrated comparable in vivo efficacy to ARS-1620, the optimized KRasG12C inhibitor which served as a prototype for those molecules that reached the clinic. Our results suggest that CFL-120 and CFL-137 being new specific KRasG12C inhibitor chemotypes demonstrating promising cellular and in vivo efficacy that nominates them for further optimization. The publication can be accessed under the following link. PreviousNext

Published a new study on Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy

10/02/2023 Publications Published a new study on Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy KINETO Lab took a part in development of Bombesin-Based Peptide–Drug Conjugates, acting as drug delivery systems to safely reach the tumour environment. Two of bioconjugates revealed remarkable anti-proliferative activity, an efficient uptake by all three tested human breast and prostate cancer cell lines, high stability in plasma and a prompt release of the drug-containing metabolite by lysosomal enzymes. Moreover, they revealed a safe profile and a consistent reduction of the tumour volume in vivo. The publication can be accessed under the following link. PreviousNext