KRAS, a prominent oncogene with high mutation rates in various cancers, was long deemed impervious to drug targeting. However, recent scientific breakthroughs have paved the way for the development of therapies specifically designed to combat KRAS mutations, particularly the challenging G12C, G12D, and G13D variants.
At Medicilon, we pride ourselves on offering a comprehensive suite of preclinical services tailored to support the discovery and development of drugs targeting KRAS mutations. Our services span the entire drug development spectrum, encompassing drug discovery, CMC research, pharmacodynamics studies, pharmacokinetics analyses, and safety evaluations.
Understanding the intricate workings of KRAS is pivotal in formulating effective therapeutic strategies. KRAS operates as a molecular switch, toggling between an inactive GDP-bound state and an active GTP-bound state. Activation of KRAS triggers signaling cascades that fuel cell growth, survival, and metastasis, underscoring its significance in cancer progression.
🔬 Crystallization & Structural Studies: Leveraging advanced synchrotron radiation facilities, our team delves into the structural nuances of KRAS. We have successfully crystallized KRAS^G12D independently and in conjunction with inhibitors like MRTX1133, shedding light on potential drug interactions at a molecular level.
🧪 Functional Assays Galore: From 2D/3D proliferation assays using CellTiter-Glo to cytotoxicity evaluations in KRAS-mutant cell lines such as NCI-H358 and MIA PaCa-2, our repertoire includes a diverse array of functional assays. Additionally, our protein-based assays, including GTP exchange, SOS1 binding, and nucleotide displacement assays, offer valuable insights into KRAS signaling dynamics.
🐭 In Vivo Modeling Excellence: Our utilization of CDX/PDX models harboring various KRAS mutations (G12C, G12D, G12V, G13D) enables us to simulate the complex tumor microenvironment and assess drug efficacy in a preclinical setting. Furthermore, our development of resistance models through in vivo selection mimics the challenging landscape of acquired drug resistance.
📊 Pharmacokinetic Proficiency: A cornerstone of our services lies in conducting detailed pharmacokinetic (PK) studies to inform candidate optimization. For instance, our evaluation of Compound 17f, a potent KRAS-PDEδ PROTAC degrader, in SD rats following ip administration at 50 mg/kg showcases our expertise in PK profiling for novel compounds.
The success stories of XNW14010, a KRAS^G12C inhibitor that entered clinical trials in 2022 with Medicilon’s PK and safety backing, and GFH925/IBI351 (Dabote®), approved in 2024 for KRAS^G12C NSCLC with early PK services provided by Medicilon, underscore our pivotal role in advancing KRAS-targeted therapies from bench to bedside.
By amalgamating profound KRAS expertise with cutting-edge platforms, Medicilon serves as a catalyst in expediting the development of therapies for historically intractable KRAS mutations, ushering in a new era of precision medicine in oncology.
Takeaways:
– Medicilon’s integrated preclinical services offer a robust foundation for the discovery and development of KRAS-targeted therapies.
– Our expertise spans a wide array of functional assays, in vivo modeling, and pharmacokinetic studies crucial for optimizing drug candidates.
– The success stories of XNW14010 and GFH925/IBI351 exemplify Medicilon’s pivotal role in advancing novel therapies for challenging KRAS mutations.
– Contact us today to embark on a transformative journey towards conquering the complexities of KRAS-driven cancers.
Tags: formulation, clinical trials
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