MRTX0902, a novel SOS1 inhibitor, is currently being evaluated in phase I trials for the treatment of cancer. The complexity molecule, which contains pyrido[3,4-d]pyridazine core and chiral amine moiety, makes it challenging target to prepare on multi-kilogram scale support clinical development studies. An efficient scalable synthesis key intermediate 4-methyl-7-morpholinopyrido[3,4-d]pyridazin...

INTRODUCTION The small G-proteins KRas, HRas, and NRas function as GDP–GTP regulated binary switches in many signal transduction pathways that govern cell growth and differentiation. Alternation between the GDP-bound ‘off’ state and the GTP-bound ‘on’ state is controlled by the guanine nucleotide exchange factors (GEFs) SOS1 and SOS2, which catalyze the exchange of GDP for GTP, and by GTPase-ac...

The increasing prevalence of soil salinity is one of the most significant obstacles to improving crop productivity. Recent advances in genetic and molecular analysis of Arabidopsis thaliana mutants, ion transporters and stress signaling proteins have improved our understanding of the mechanisms of cellular ion homeostasis and its regulation in plants. Since Na toxicity is the principal stress c...

Vav and Sos1 are Dbl family guanine nucleotide exchange factors, which activate Rho family GTPases in response to phosphatidylinositol 3-kinase products. A pleckstrin homology domain adjacent to the catalytic Dbl homology domain via an unknown mechanism mediates the effects of phosphoinositides on guanine nucleotide exchange activity. Here we tested the possibility that phosphatidylinositol 3-k...

Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) ...

Genetic and physiological data establish that Arabidopsis AtHKT1 facilitates Na(+) homeostasis in planta and by this function modulates K(+) nutrient status. Mutations that disrupt AtHKT1 function suppress NaCl sensitivity of sos1-1 and sos2-2, as well as of sos3-1 seedlings grown in vitro and plants grown in controlled environmental conditions. hkt1 suppression of sos3-1 NaCl sensitivity is li...

The salt tolerance of rice (Oryza sativa) correlates with the ability to exclude Na+ from the shoot and to maintain a low cellular Na+/K+ ratio. We have identified a rice plasma membrane Na+/H+ exchanger that, on the basis of genetic and biochemical criteria, is the functional homolog of the Arabidopsis (Arabidopsis thaliana) salt overly sensitive 1 (SOS1) protein. The rice transporter, denoted...

Chlamydia trachomatis attachment to cells induces the secretion of the elementary body-associated protein TARP (Translocated Actin Recruiting Protein). TARP crosses the plasma membrane where it is immediately phosphorylated at tyrosine residues by unknown host kinases. The Rac GTPase is also activated, resulting in WAVE2 and Arp2/3-dependent recruitment of actin to the sites of chlamydia attach...

Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition t...