A5022776516- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- ATP Synthase and ATPases Research
- Mechanisms of cancer metastasis
- Protein Tyrosine Phosphatases
- Signaling Pathways in Disease
- Protein Kinase Regulation and GTPase Signaling
- Melanoma and MAPK Pathways
- PI3K/AKT/mTOR signaling in cancer
- Ubiquitin and proteasome pathways
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Biochemical and Molecular Research
- Peptidase Inhibition and Analysis
- Galectins and Cancer Biology
- Cancer Mechanisms and Therapy
- Microtubule and mitosis dynamics
- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Cytokine Signaling Pathways and Interactions
- 14-3-3 protein interactions
- Synthesis and biological activity
- Protein Degradation and Inhibitors
- Enzyme Structure and Function
- Bioactive Compounds and Antitumor Agents
Revolution Medicines (United States)
2017-2025
Royal North Shore Hospital
2019
AstraZeneca (United Kingdom)
2011-2014
AstraZeneca (Sweden)
2014
Roche (United States)
2010
Institute of Cancer Research
2009
Cancer Research UK
2009
Newcastle University
2006
University of Hertfordshire
2001
University of Sussex
2001
Here, we describe the identification of a clinical candidate via structure-based optimization ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play key role in regulation mitosis and recent years have become attractive targets for treatment cancer. X-ray crystallographic structures were generated using novel soakable form A used to drive toward potent (IC(50) approximately 3 nM) dual A/Aurora B inhibitors. These compounds inhibited growth survival HCT116 cells produced...
The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, active state mutant such a recalcitrant target. We designed natural product–inspired small molecule remodels surface cyclophilin A (CYPA) to create neomorphic interface with high affinity selectivity G12C (in which...
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...
The discovery of elironrasib (RMC-6291) represents a significant breakthrough in targeting the previously deemed undruggable GTP-bound, active KRASG12C. To target state RAS (RAS(ON)) directly, we have employed an innovative tri-complex inhibitor (TCI) modality involving formation complex with inhibitor, intracellular chaperone protein CypA, and KRASG12C its GTP-bound form. resulting inhibits oncogenic signaling, inducing tumor regressions across various preclinical models mutant human...
We describe the structure-guided optimization of molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 35 microM) identified using X-ray crystallographic screening p38alpha MAP kinase. Using two separate case studies, article focuses on key compounds synthesized, structure-activity relationships binding mode observations made during this process, resulting in potent lead series that demonstrate significant increases activity. process compound...
Abstract The protein tyrosine phosphatase SHP2 binds to phosphorylated signaling motifs on regulatory immunoreceptors including PD-1, but its functional role in tumor immunity is unclear. Using preclinical models, we show that RMC-4550, an allosteric inhibitor of SHP2, induces antitumor immunity, with effects equivalent or greater than those resulting from checkpoint blockade. In the microenvironment, inhibition modulated T-cell infiltrates similar addition, RMC-4550 drove direct, selective...
Abstract KRASG12D is the most frequent KRAS mutation in human cancers, with highest prevalence pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung (NSCLC). RMC-9805 a first-in-class, oral, mutant-selective covalent inhibitor of GTP-bound active RAS(ON) form KRASG12D. The formation stable, high affinity tri-complex between RMC-9805, cyclophilin A results suppression signaling downstream KRASG12D(ON) by disrupting its interactions effectors such as RAF...
Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or crosstalk with other mutant cancer drivers, such as RAS, is a feature many tumors. Multiple allosteric inhibitors mTORC1 and orthosteric dual mTORC2 have been developed anticancer drugs, but their clinical utility has limited. To address these limitations, we novel class "bi-steric inhibitors" that interact both binding sites order to deepen inhibition while also preserving selectivity for over mTORC2. In this report,...
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...
A matched molecular series is the general form of a pair and refers to set two or more molecules with same scaffold but different R groups at position. We describe Matsy, knowledge-based method that uses predict likely improve activity given an observed order for some groups. compare Matsy predictions based on data from ChEMBLdb recommendations Topliss tree carry out large scale retrospective test measure performance. show basis predictive success preferred orders in this preference stronger...
Abstract The KRASG12C mutation is found in 11% of non-small cell lung cancers, 4% colorectal and 2% pancreatic cancers the U.S., drives these by shifting cellular equilibrium KRAS towards GTP-bound, active state, KRASG12C(ON). resulting increased levels KRASG12C(ON) turn increase signaling output to initiate support oncogenic state. In recent years, a class KRASG12C(OFF) inhibitors has transformed treatment landscape for patients with bearing KRASG12C. These work via sequestration GDP-bound,...
Abstract KRASG12D mutant cancers represent a significant unmet medical need with 55,000 new diagnoses annually in the US. The mutation occurs commonly multiple tumor histotypes, including about 20%, 29% and 17% of KRAS colorectal, pancreatic, non-small cell lung cancers, respectively. However, there are no directly targeted inhibitors clinical development. Mutant RAS proteins exist predominantly GTP-bound RAS(ON) state, leading to excessive downstream signaling via interaction effectors such...
M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme DNA synthesis. In order identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and NMR based fragment through which discovered two classes of inhibitors, 3-cyanopyridones 1,6-naphthyridin-2-ones, respectively. We describe three cyanopyridone subseries that arose during our hit lead campaign, along with cocrystal structures representatives TMK. Structure aided...
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...
Abstract RASG12D mutant cancers represent a significant unmet medical need with 55,000 new diagnoses annually in the US. The mutation increases abundance of active, GTP-bound state RAS (RASG12D(ON)) and occurs commonly multiple tumor histotypes, including about 20%, 29% 17% colorectal, pancreatic, non-small cell lung cancers, respectively. RMC-6236, an investigational RASMULTI(ON) inhibitor currently clinical testing, selectively targets both wild-type variants, RASG12D(ON) has shown...
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)...
Agonists of vasoactive intestinal peptide receptor 2 (VPAC2) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment hyperglycaemia and type-II diabetes. Vasoactive (VIP) is an endogenous hormone that potently agonizes VPAC2. However, VIP has a short serum half-life poor pharmacokinetics in vivo susceptible to proteolytic degradation, its development as therapeutic agent challenging. Here, we investigated two cyclization strategies, lactamisation...
BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as downstream effector RAS, potential therapeutic target in melanoma. We have developed series small-molecule BRAF inhibitors based on 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) hinge binding moiety number substituted phenyl rings C interact with allosteric site. The introduction various groups central ring B combined appropriate A- C-ring modifications afford very potent compounds inhibit...