Faculty Opinions recommendation of Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.

AbstractColorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

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Faculty Opinions recommendation of Allele-specific inhibitors of protein tyrosine phosphatases.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1024538.288002 ◽

2005 ◽

Author(s):

Amy Barrios

Keyword(s):

Protein Tyrosine Phosphatases ◽

Tyrosine Phosphatases ◽

Protein Tyrosine ◽

Allele Specific ◽

Specific Inhibitors

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Allele-Specific Inhibitors of Protein Tyrosine Phosphatases

Journal of the American Chemical Society ◽

10.1021/ja043378w ◽

2005 ◽

Vol 127 (9) ◽

pp. 2824-2825 ◽

Cited By ~ 20

Author(s):

Hillary E. Hoffman ◽

Elizabeth R. Blair ◽

James E. Johndrow ◽

Anthony C. Bishop

Keyword(s):

Protein Tyrosine Phosphatases ◽

Tyrosine Phosphatases ◽

Protein Tyrosine ◽

Allele Specific ◽

Specific Inhibitors

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Design of allele-specific inhibitors to probe protein kinase signaling

Current Biology ◽

10.1016/s0960-9822(98)70198-8 ◽

1998 ◽

Vol 8 (5) ◽

pp. 257-266 ◽

Cited By ~ 149

Author(s):

Anthony C. Bishop ◽

Kavita Shah ◽

Yi Liu ◽

Laurie Witucki ◽

Chi-yun Kung ◽

...

Keyword(s):

Protein Kinase ◽

Kinase Signaling ◽

Allele Specific ◽

Protein Kinase Signaling ◽

Specific Inhibitors

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Observation of Superlattice Dislocations on Cube Planes in Ni3Al

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100071314 ◽

1973 ◽

Vol 31 ◽

pp. 174-175 ◽

Cited By ~ 1

Author(s):

J. M. Oblak ◽

W. H. Rand

Keyword(s):

Nearest Neighbor ◽

Antiphase Boundary ◽

Nearest Neighbors ◽

High Energy ◽

Cross Slip ◽

Octahedral Plane ◽

Trapping Mechanism ◽

Slip Traces

The energy of an a/2 <110> shear antiphase. boundary in the Ll2 expected to be at a minimum on {100} cube planes because here strue ture is there is no violation of nearest-neighbor order. The latter however does involve the disruption of second nearest neighbors. It has been suggested that cross slip of paired a/2 <110> dislocations from octahedral onto cube planes is an important dislocation trapping mechanism in Ni3Al; furthermore, slip traces consistent with cube slip are observed above 920°K.Due to the high energy of the {111} antiphase boundary (> 200 mJ/m2), paired a/2 <110> dislocations are tightly constricted on the octahedral plane and cannot be individually resolved.

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Improved method for generation of HLA-DR allele specific monoclonal antibodies using phage libraries

Immunology Letters ◽

10.1016/s0165-2478(97)88352-6 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 375

Author(s):

B Hansen

Keyword(s):

Monoclonal Antibodies ◽

Improved Method ◽

Hla Dr ◽

Allele Specific ◽

Phage Libraries

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Localization of the Br Polymorphism on a 144 bp Exon of the GPIa Gene and Its Application in Platelet DNA Typing

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642498 ◽

1994 ◽

Vol 71 (05) ◽

pp. 651-654 ◽

Cited By ~ 50

Author(s):

Rainer Kalb ◽

Sentot Santoso ◽

Katja Unkelbach ◽

Volker Kiefel ◽

Christian Mueller-Eckhardt

Keyword(s):

Genomic Organization ◽

Fragment Length Polymorphism ◽

Human Platelet ◽

Dna Typing ◽

Rflp Analysis ◽

Serological Typing ◽

Allele Specific ◽

Polymerase Chain ◽

Alloimmune Thrombocytopenia ◽

Rflp Typing

SummaryAlloimmunization against the human platelet alloantigen system Br (HPA-5) is the second most common cause of neonatal alloimmune thrombocytopenia (NAIT) in Caucasian populations. We have recently shown that a single base polymorphism at position 1648 on platelet mRNA coding for GPIa results in an aminoacid substitution at position 505 on the mature GPIa which is associated with the two serological defined Br phenotypes.Since DNA-typing of platelet alloantigens offers possibilities for useful clinical applications, we designed genomic DNA-based restriction fragment length polymorphism (RFLP) typing for Br alloantigens. To establish this technique we analyzed the genomic organization of GPIa adjacent to the polymorphic base. Using the polymerase chain reaction (PCR) of blood cell DNA we have identified two introns (approximately 1.7 and 1.9 kb) flanking a 144 bp coding sequence of the GPIa gene encompassing the polymorphic base 1648. Based on the in- tron sequence, a PCR primer was constructed to amplify a 274 bp fragment which was used for allele-specific RFLP to determine the Br genotypes. The results of RFLP analysis using Mnll endonuclease obtained from 15 donors (2 Br37*, 2 Br^ and 11 Brb/b) correlate perfectly with serological typing by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay.

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