Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical ...cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.
Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following ...initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.
K-RAS is mutated in approximately 30% of human cancers, resulting in increased RAS signaling and tumor growth. Thus, RAS is a highly validated therapeutic target, especially in tumors of the ...pancreas, lung and colon. Although directly targeting RAS has proven to be challenging, it may be possible to target other proteins involved in RAS signaling, such as the guanine nucleotide exchange factor Son of Sevenless (SOS). We have previously reported on the discovery of small molecules that bind to SOS1, activate SOS-mediated nucleotide exchange on RAS, and paradoxically inhibit ERK phosphorylation (Burns et al., PNAS, 2014). Here, we describe the discovery of additional, structurally diverse small molecules that also bind to SOS1 in the same pocket and elicit similar biological effects. We tested >160,000 compounds in a fluorescence-based assay to assess their effects on SOS-mediated nucleotide exchange. X-Ray structures revealed that these small molecules bind to the CDC25 domain of SOS1. Compounds that elicited high levels of nucleotide exchange activity in vitro increased RAS-GTP levels in cells, and inhibited phospho ERK levels at higher treatment concentrations. The identification of structurally diverse SOS1 binding ligands may assist in the discovery of new molecules designed to target RAS-driven tumors.
•Measured nucleotide exchange rate with a high-throughput fluorescence-based assay.•Discovered structurally diverse molecules that activate nucleotide exchange.•Used X-Ray structures to determine that molecules bind to the CDC25 domain of SOS1.•Identified that molecules modulate RAS-GTP and phospho ERK levels in cancer cells.
Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has ...yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2
protein levels at higher compound concentrations.
A highly stereoselective synthesis of a model C(18)-C(35) spiroketal unit (7) of integramycin has been accomplished via an enantioselective stannyl-crotylboration reaction and an ...N-iodosuccinimide-mediated spiroketalization of 19a.
Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have ...proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.
A stereoselective synthesis of a fully protected version of the disaccharide unit (2) of incednine (1) is described. The synthesis of 2 proceeds in 4.7% overall yield from commercially available ...allyl α-d-galactopyranoside over the longest linear sequence.
Transformative changes in health professions education need to incorporate effective faculty development, but few very large-scale faculty development designs have been described. The Royal College ...of Physicians and Surgeons of Canada's Competence by Design project was launched to transform the delivery of postgraduate medical education in Canada using a competency-based model. In this paper we outline the goals, principles, and rationale of the Royal College's national strategy for faculty and resident development initiatives to support the implementation of Competence by Design. We describe the activities and resources for both faculty and trainees that facilitated the redesign of training programs for each specialty and subspecialty at the national level, as well as supporting the implementation of the redesign at the local level. This undertaking was not without its challenges: we thus reflect on those challenges, enablers, and the lessons learned, and discuss a continuous quality improvement approach that was taken to iteratively inform the implementation process moving forward.
Blending a shape‐memory polymer (SMP) (e.g., thermoplastic polyurethane) with an immiscible carrier polymer (e.g., poly(ethylene oxide) (PEO) or poly(vinyl alcohol) (PVA)) containing dispersed metal ...nanoparticles (AuNPs) is a simple approach to enable actuation via photothermal heating. For blends containing up to 90% carrier polymer, the shape‐memory capability can be thermally triggered either conventionally or utilizing internal heating via application of light that is resonant with the particle's surface plasmon resonance. When incorporating nanoparticles in this manner, neither chemical modification of the shape‐memory moiety nor solvation of the SMP is necessary. Actuation times are determined by the particular heterogeneous temperature distribution, which generally occurs under both conventional and photothermal heating methods, but with different spatial patterns. Blending an SMP with PEO containing AuNPs imposes a higher transition temperature (the melting point of PEO), enabling heat generated within the nanoparticle‐containing regions to equilibrate throughout the sample, resulting in performance under photothermal conditions comparable with that achieved in a conventional heating approach. SMP:PVA blends actuate at the SMP transition temperature and the response depends on the size of phase segregation between the PVA and SMP; when decreasing the characteristic size of the segregated regions, heat is efficiently transferred and optimal photothermal performance is observed.
Blending shape‐memory materials with a compatible carrier polymer containing metal nanoparticles enables wavelength‐specific light‐to‐heat triggering. Particles utilized as nanoscale heaters are contained within the carrier polymer, which will act as either “soft”, “hard”, or inert phases with respect to the actuation, having differing advantages and challenges in each case.
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