CYPA

Researchers have discovered that the enzyme cyclophilin A, which is produced in large amounts in hematopoietic stem cells, is key for these cells to retain their regenerative potential and avert the effects of aging via an unexpected mechanism. Nothing lives forever, but compared to other cells in the body, hematopoietic stem cells (HSCs) are remarkably long-lived. HSCs are blood-forming cells -- they give rise to rapidly dividing progenitor cells, which in turn generate hundreds of billions of cells to fulfill the daily demand of oxygen-delivering red blood cells, disease-fighting white blood cells and clot-forming platelets. HSCs typically remain dormant within the bone marrow, yet they possess the ability to activate and replenish blood cells continuously, maintaining a relatively youthful pro the life of an organism. What is the secret of long-lived HSCs that wards off the effects of aging? A team led by researchers at Baylor College of Medicine revealed in Nature Cell Biology that the enzyme cyclophilin A, which is produced in large amounts in HSCs, is key for these cells to retain their regenerative potential and avert the effects of aging. Long live the stem cells! "A driving force of cellular aging is the accumulation of proteins that have reached the end of their useful life," said corresponding author Dr. André Catic, assistant professor and CPRIT Scholar in Cancer Research in the Huffington Center on Aging at Baylor. "With age, proteins tend to misfold, aggregate and accumulate inside the cell, which leads to toxic stress that can disrupt cell function." Cells that frequently engage in cell division, like progenitor cells, can dispose of protein aggregates through dilution. On the other hand, long-lived HSCs, which do not divide often, face the problem of the accumulation of misfolded proteins and subsequent toxic stress. Nevertheless, HSCs remain impervious to aging. How do they do it? "Understanding the molecular mechanisms that contribute to HSC aging not only contributes to the field of normal HSC biology, but also may have significant clinical relevance for cancer treatment," said co-first author of the work, Dr. Lauren Maneix, who was at the Catic lab while working on this project. Molecular chaperones at work Previous studies have shown that mammalian cells express several hundreds of molecular chaperones, proteins that preserve or change the three-dimensional conformation of existing proteins. Cyclophilins, one of the most abundant chaperones, have been implicated in the aging process. However, how they affect cellular proteins has not previously been studied. Working with mice, the researchers first characterized the protein content of HSCs and discovered that cyclophilin A is a prevalent chaperone. Further experiments showed that the expression of cyclophilin A was significantly decreased in aged HSCs, and genetically eliminating cyclophilin A accelerated natural aging in the stem cell compartment. In contrast, reintroducing cyclophilin A into aged HSCs enhanced their function. Together, these findings support cyclophilin A as a key factor in the longevity of HSCs. Connecting cyclophilin A, intrinsically disordered proteins and HSC longevity Next, the team investigated the proteins with which cyclophilin A interacts, preserving their stability. "We found that proteins enriched in intrinsically disordered regions are frequent targets of the chaperone," Catic said. Intrinsically disordered proteins naturally change their 3-D conformation to interact with different proteins, nucleic acids or other molecules. Consequently, proteins rich in intrinsically disordered regions regulate many cellular processes by promoting specific activities between molecules. "Due to their flexible nature, intrinsically disordered proteins are inherently prone to aggregation. Cyclophilin A supports these proteins in fulfilling their functions and simultaneously prevents them from clumping," Catic said. Furthermore, the findings suggest that cyclophilin A interacts with intrinsically disordered proteins from the moment of their synthesis. "As these proteins are being made, cyclophilin A makes sure they keep the appropriate conformations and are maintained at sufficient levels," Catic said. "Genetic depletion of cyclophilin A results in stem cells distinctively lacking intrinsically disordered proteins." "For the first time, our study showed that producing disordered proteins and maintaining the structural diversity of the proteins in a cell plays a role in HSC aging," Maneix said. Co-first author Polina Iakova, Charles G. Lee, Shannon E. Moree, Xuan Lu, Gandhar K. Datar, Cedric T. Hill, Eric Spooner, Jordon C. K. King, David B. Sykes, Borja Saez, Bruno Di Stefano, Xi Chen, Daniela S. Krause, Ergun Sahin, Francis T. F. Tsai, Margaret A. Goodell, Bradford C. Berk and David T. Scadden also contributed to this study.

SHANGHAI and SAN DIEGO, April 9, 2024 /PRNewswire/ -- GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, today announced the latest findings of GFH547, an oral panRAS (ON) inhibitor, in a late-breaking research abstract at the 2024 American Association for Cancer Research (AACR) Annual Meeting. GFH547 is developed with novel mechanism of action by reshaping and repurposing intracellular cyclophilin A (CypA) protein to target active RAS proteins across most wild/mutant subtypes. Preclinical data demonstrated profound panRAS inhibitory activity of GFH547 and it holds the potential to overcome adaptive and acquired resistance against SIIP (switch II pocket)-based KRAS inhibitors. "Secondary mutations detected among subjects in clinical studies of KRAS inhibitors have paved the way for the development of future therapies, and GFH547 is anticipated as a new-generation inhibitor to combat the drug resistance. GenFleet's KRAS G12C inhibitor (GFH925) has had its New Drug Application accepted with Priority Review Designation in China. From the first-generation KRAS inhibitor to a new-generation pan-RAS inhibitor, the continuous achievements underscore GenFleet's insight into the development of RAS pathway targeted therapies. The top-tier development also showcases the depth of GenFleet's cutting-edge pipeline and its value potential." stated Fusheng Zhou, Ph.D., Vice President of GenFleet's Drug Discovery Department. Abstract Title: GFH547: An orally bioavailable, cyclophilin A-hijacking panRAS (ON) inhibitor with broad spectrum anti-tumor activities Abstract No.: LB165/11 The GFH547-Cyp A-RAS tripartite complex inhibits most wild/mutant subtypes of active, GTP-bound RAS proteins GFH547 has demonstrated preliminary efficacy to inhibit RAS proteins across most subtypes including the KRAS mutant proteins commonly found in human tumors (especially harboring G12C, G12D and G12V mutations). Compared with targeting RAS proteins or the RAS-RAF complex alone, the recruitment of CypA into the tripartite complex induces more profound inhibition of RAS pathway (including the RAS proteins and their downstream interaction with RAF). The deep inhibition of KRAS pathway was observed following a single oral administration of GFH547 in KRAS mutant CDX tumors. GFH547 also demonstrates dose-dependent anti-tumor activity and drives tumor regression in KRAS mutant tumor models. GFH547 is superior to the mainstream SIIP-based KRAS inhibitors in overcoming adaptive and acquired resistance GFH547 is resistant to RTK activation by EGF stimulation which attenuates potency of current mainstream SIIP-based KRAS inhibitors. It is also effective to cells carrying secondary KRAS mutations causing acquired resistance to SIIP-based KRAS inhibitors. Overall, GFH547 demonstrates promising bioavailability, kinase selectivity and safety in the preclinical research. About RAS and GFH457 RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK、PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans. GFH547 is a novel small-molecule panRAS (ON) inhibitor hijacking Cyp A to target active, GTP bound RAS proteins of most wild/mutant subtypes, including most commonly found KRAS mutant (G12C, G12D, G12V, etc.) proteins. Preclinical research of GFH547 demonstrates dose-dependent anti-tumor activity and drives tumor regression in multiple KRAS mutant tumor models. GFH547 is also superior to the mainstream SIIP (switch II pocket)-based KRAS inhibitors in overcoming adaptive and acquired resistance. About GenFleet Therapeutics GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies, is dedicated to serving significant global unmet medical needs in oncology and immunology. Based on the deep understanding of disease biology and translational medicine, GenFleet's proprietary and fully integrated R&D platform highlights multiple cutting-edge products with novel mechanisms and global IP. Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates - both small molecules and biologics. Its pipeline includes over 10 programs, many of which have entered multi-regional clinical trials across China (including Taiwan), the United States, Europe and Australia. To date, GenFleet has over 5 clinical studies encompassing IND stage to phase II studies and completed co-development partnerships with numerous publicly listed companies worldwide. GenFleet is expected to progress additional programs into the clinic, as well as transition from a clinical stage biotech company into a commercial stage biopharmaceutical company in the next 3-5 years. SOURCE GenFleet Therapeutics

SHANGHAI and SAN DIEGO, April 9, 2024 /PRNewswire/ -- GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, today announced the latest findings of GFH547, an oral panRAS (ON) inhibitor, in a late-breaking research abstract at the 2024 American Association for Cancer Research (AACR) Annual Meeting. GFH547 is developed with novel mechanism of action by reshaping and repurposing intracellular cyclophilin A (CypA) protein to target active RAS proteins across most wild/mutant subtypes. Preclinical data demonstrated profound panRAS inhibitory activity of GFH547 and it holds the potential to overcome adaptive and acquired resistance against SIIP (switch II pocket)-based KRAS inhibitors. "Secondary mutations detected among subjects in clinical studies of KRAS inhibitors have paved the way for the development of future therapies, and GFH547 is anticipated as a new-generation inhibitor to combat the drug resistance. GenFleet's KRAS G12C inhibitor (GFH925) has had its New Drug Application accepted with Priority Review Designation in China. From the first-generation KRAS inhibitor to a new-generation pan-RAS inhibitor, the continuous achievements underscore GenFleet's insight into the development of RAS pathway targeted therapies. The top-tier development also showcases the depth of GenFleet's cutting-edge pipeline and its value potential." stated Fusheng Zhou, Ph.D., Vice President of GenFleet's Drug Discovery Department. Abstract Title: GFH547: An orally bioavailable, cyclophilin A-hijacking panRAS (ON) inhibitor with broad spectrum anti-tumor activities Abstract No.: LB165/11 The GFH547-Cyp A-RAS tripartite complex inhibits most wild/mutant subtypes of active, GTP-bound RAS proteins GFH547 has demonstrated preliminary efficacy to inhibit RAS proteins across most subtypes including the KRAS mutant proteins commonly found in human tumors (especially harboring G12C, G12D and G12V mutations). Compared with targeting RAS proteins or the RAS-RAF complex alone, the recruitment of CypA into the tripartite complex induces more profound inhibition of RAS pathway (including the RAS proteins and their downstream interaction with RAF). The deep inhibition of KRAS pathway was observed following a single oral administration of GFH547 in KRAS mutant CDX tumors. GFH547 also demonstrates dose-dependent anti-tumor activity and drives tumor regression in KRAS mutant tumor models. GFH547 is superior to the mainstream SIIP-based KRAS inhibitors in overcoming adaptive and acquired resistance GFH547 is resistant to RTK activation by EGF stimulation which attenuates potency of current mainstream SIIP-based KRAS inhibitors. It is also effective to cells carrying secondary KRAS mutations causing acquired resistance to SIIP-based KRAS inhibitors. Overall, GFH547 demonstrates promising bioavailability, kinase selectivity and safety in the preclinical research. About RAS and GFH457 RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK、PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans. GFH547 is a novel small-molecule panRAS (ON) inhibitor hijacking Cyp A to target active, GTP bound RAS proteins of most wild/mutant subtypes, including most commonly found KRAS mutant (G12C, G12D, G12V, etc.) proteins. Preclinical research of GFH547 demonstrates dose-dependent anti-tumor activity and drives tumor regression in multiple KRAS mutant tumor models. GFH547 is also superior to the mainstream SIIP (switch II pocket)-based KRAS inhibitors in overcoming adaptive and acquired resistance. About GenFleet Therapeutics GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies, is dedicated to serving significant global unmet medical needs in oncology and immunology. Based on the deep understanding of disease biology and translational medicine, GenFleet's proprietary and fully integrated R&D platform highlights multiple cutting-edge products with novel mechanisms and global IP. Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates - both small molecules and biologics. Its pipeline includes over 10 programs, many of which have entered multi-regional clinical trials across China (including Taiwan), the United States, Europe and Australia. To date, GenFleet has over 5 clinical studies encompassing IND stage to phase II studies and completed co-development partnerships with numerous publicly listed companies worldwide. GenFleet is expected to progress additional programs into the clinic, as well as transition from a clinical stage biotech company into a commercial stage biopharmaceutical company in the next 3-5 years.