Stephanie Chang
A5069084946- Cancer Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Mechanisms of cancer metastasis
- ATP Synthase and ATPases Research
- Biochemical and Molecular Research
- Protein Kinase Regulation and GTPase Signaling
- Signaling Pathways in Disease
- Cellular Mechanics and Interactions
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Cancer Mechanisms and Therapy
- Pancreatic and Hepatic Oncology Research
- Peptidase Inhibition and Analysis
- 3D Printing in Biomedical Research
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Amino Acid Enzymes and Metabolism
- Blood Coagulation and Thrombosis Mechanisms
- Melanoma and MAPK Pathways
- Cancer Genomics and Diagnostics
- Click Chemistry and Applications
- Cancer therapeutics and mechanisms
- Biochemical and Structural Characterization
- Atrial Fibrillation Management and Outcomes
- Microfluidic and Bio-sensing Technologies
Revolution Medicines (United States)
2021-2025
Pfizer (United States)
2023
Eon Corporation (United States)
2018-2020
Carnegie Mellon University
2013-2019
California Institute of Technology
2010
Abstract RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 61 1 . Small molecule inhibitors of KRAS(G12C) oncoprotein have demonstrated clinical efficacy patients multiple cancer types led to regulatory approvals for treatment non-small cell lung 2,3 Nevertheless, G12C account only around 15% -mutated cancers 4,5 there no approved majority tumours containing other...
Abstract RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor the active, GTP-bound state both mutant and wild-type variants canonical RAS isoforms with broad therapeutic potential for aforementioned unmet medical need. exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 KRAS. Notably, oral administration was tolerated in vivo drove profound tumor regressions...
Abstract Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by mutations 1,2 . RMC-7977 is highly selective inhibitor active GTP-bound forms KRAS, HRAS and NRAS, affinity for both mutant wild-type variants 3 More than 90% cases pancreatic ductal adenocarcinoma (PDAC) activating in KRAS 4 Here we assessed therapeutic comprehensive range PDAC models. We observed broad pronounced anti-tumour activity across models...
Abstract Mutant RAS is common in pancreatic carcinoma (PDAC), non-small cell lung cancer (NSCLC) and colorectal (CRC) exists predominantly the GTP-bound (RAS(ON)) state, leading to excessive downstream oncogenic signaling. KRASG12C(OFF) inhibitors have provided clinical proof of concept for targeting mutant KRAS. Preclinical data suggests inhibition RAS(ON) may be a superior therapeutic strategy. In addition, KRASG12 mutations such as KRASG12D KRASG12V remain unserved.RMC-6236...
Abstract KRASG12V mutant cancers represent a significant unmet medical need with nearly 44,000 new diagnoses annually in the US. The mutation occurs frequently multiple tumor histotypes; incidence NSCLC, CRC and pancreatic is 6%, 10% 26%, respectively. RAS proteins are small GTPases that drive cell proliferation survival when bound to GTP. Mutant exist predominantly GTP-bound (RAS(ON)) state, leading excessive downstream signaling via interaction effectors such as RAF. intrinsic GTP...
591 Background: RAS proteins (such as KRAS, NRAS, HRAS) are small GTPases that drive cell proliferation and survival when bound to GTP. Mutant exist predominantly in the GTP-bound (RAS(ON)) state, leading excessive downstream signaling via interaction with effectors such RAF kinases. Oncogenic KRAS is required for initiation, progression, maintenance of pancreatic ductal adenocarcinoma (PDAC) (Hezel et al, 2006, Ying al 2012). Although extinction expression well pharmacological inhibition...
Oncogenic RAS mutations are among the most common in human cancers. To target active, GTP-bound state of RAS(ON) directly, we employed an innovative tri-complex inhibitor (TCI) modality. Formation a complex with intracellular chaperone protein CypA, inhibitor, and blocks effector binding, inhibiting downstream signaling tumor cell proliferation. Herein, describe structure-guided SAR journey that led to discovery daraxonrasib (RMC-6236), noncovalent, potent multiple mutant wild-type (WT)...
Simple geometrical constraints of micropatterned substrates can be used to manipulate the direction and directional persistence motile cells (scale bar: 20 μm). Modulation bias is demonstrated by altering pattern parameters signal pathways. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made available submitted authors. Please note: The publisher responsible for content functionality...
Cell migration has a profound effect on the generation of traction forces and phosphorylation focal adhesion proteins. The mechanism may involve dynamic turnover adhesions during cell mechanical interactions between nascent preexisting adhesions.
Abstract The degradation tag (dTAG) system for target protein can remove proteins from biological systems without the drawbacks of some genetic methods, such as slow kinetics, lack reversibility, low specificity, and inability to titrate dosage. These make it difficult compare toxicity resulting pharmacological interventions, especially in vivo. Because dTAG has not been studied extensively vivo, we explored use this study physiological sequalae CDK2 or CDK5 adult mice. Mice with homozygous...
Summary Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by mutations. However, impact inhibiting functions in normal tissues is not known. RMC-7977 highly selective inhibitor active (GTP-bound) forms KRAS, HRAS, and NRAS, with affinity for both mutant wild type (WT) variants. As >90% pancreatic ductal adenocarcinoma (PDAC) cases activating mutations KRAS , we assessed therapeutic comprehensive range PDAC...
Introduction In recent years, the traditional treatments for thrombotic diseases, heparin and warfarin, are increasingly being replaced by novel oral anticoagulants offering convenient dosing regimens, more predictable anticoagulant responses, less frequent monitoring. However, these drugs can be contraindicated some patients and, in particular, their bleeding liability remains high. Methods We have developed a new class of direct thrombin inhibitors (VE-DTIs) utilized kinetics, biochemical,...
<p>Supplementary Figure 1 shows RMC-6236 crystal structure in tri-complex, as well biophysical and cellular potencies of by genotype. Supplementary 2 demonstrates dose-dependent anti-tumor activities at tolerable doses; pharmacodynamic effects on RAS signaling NCI-H441 xenograft tumors assessed IHC, relatively refractory KP-4 NCI-H2122 human DUSP6 mRNA expression vivo. 3 genotype dependent response across NSCLC, PDAC CRC; potential modifiers to the durability KRASG12C NSCLC models upon...
Abstract KRASQ61H mutant cancers represent a significant unmet medical need and include common solid tumor histotypes such as non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC). Currently, there are no targeted inhibitors of in clinical development. Mutant RAS proteins exist predominantly the GTP-bound active RAS(ON) state, leading to excessive downstream signaling via interaction with effectors RAF kinases. The properties intrinsic GTPase cycle...
Abstract RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 61 1 . Small molecule inhibitors of G12C oncoprotein have demonstrated clinical efficacy patients multiple cancer types led to regulatory approvals for treatment non-small-cell lung (NSCLC) 2,3 Nevertheless, account only ~14% cancers 4 there no approved majority tumors harboring other mutations. Here, we describe...
Abstract RM-042 is a broad-spectrum inhibitor of the active (GTP-bound) form KRAS, HRAS, and NRAS, with affinity for both mutant wild type (WT) variants (RASMULTI(ON)). Given that more than 90% human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in we assessed therapeutic potential comprehensive range PDAC models, including murine cell lines, patient-derived organoids, explants, subcutaneous orthotopic cell-line or patient derived xenografts, syngeneic...
Abstract Inhibitors of the GDP-bound state mutant KRASG12C protein (KRASG12C(OFF)), e.g., adagrasib and sotorasib, have shown clinical activity in patients with KRASG12C-driven NSCLC, CRC PDAC. However, most exhibit progression on monotherapy treatment months, underlining need for combination therapeutic approaches that improve durability anti-tumor seen inhibitors. RMC-6291 is a mutant-selective covalent inhibitor GTP-bound RAS(ON) form RASG12C, while RMC-6236 non-covalent RASMULTI(ON) both...
Abstract More than 90% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS that drive it into an active, GTP-bound state (KRAS(ON)), producing excessive signaling via MAPK and other effector pathways. RMC-7977 is a potent inhibitor RAS proteins (RAS(ON)), including both wild type mutant variants KRAS, NRAS, HRAS. The related investigational agent, RMC-6236, first-in-class, potent, orally bioavailable, RASMULTI(ON) currently Phase 1/1b clinical trials...