mutant Kras inhibitor in cancer cells is working

pujixing

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism3 i; ?% q1 w; W7 u( G, ?4 R# g
Piro Lito,1* Martha Solomon,2 Lian-Sheng Li,3 Rasmus Hansen,3 Neal Rosen1,2*
, P! ?0 n, B' h# E- A6 B1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3Wellspring Biosciences, La Jolla, CA, USA.
, X: M5 \/ J7 b- R2 f  [0 H*Corresponding author. E-mail: rosenn@mskcc.org (N.R.); litop@mskcc.org (P.L.)2 H2 y: J0 K& w- L
It is believed that KRAS oncoproteins are constitutively active because their GTPase activity is disabled. With this in mind, drugs targeting the inactive or GDP-bound conformation are not expected to be effective. We now describe a mechanism that enables such drugs to inhibit KRASG12C-signaling and cancer cell growth. Inhibition requires intact GTPase activity and occurs because drug-bound KRASG12C is insusceptible to nucleotide exchange factors and thus trapped in its inactive state. Indeed, mutants completely lacking GTPase activity and those promoting exchange reduced the potency of the drug. Suppressing nucleotide exchange activity downstream of various tyrosine-kinases enhanced KRASG12C inhibition, whereas its potentiation had the opposite effect. These findings reveal that KRASG12C undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRASG12C-driven cancers.
6 e3 d: J7 |5 r8 `5 y9 ?
7 z) v) Y/ A( i0 x2 _突破传统观点（认为Kras作为癌症治疗的靶标不具有可操作性），该论文从功能学证明了靶向抑制Kras G12C的药物ARS853具有剂量依赖的Kras信号通路的阻断作用。

shunho-cell

好像看 包包不够