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Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3Ks role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110a and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.Competing Interest StatementJ.E.K., N.R., S.M.B., S.G., M.A.H., H.M., J.T., J.W., C.B., A.E.O., R.L., Y.L., M.P., H.P., I.M., A.N.S., E.J.W., T.E.W., E.A., K.B., B.D.H., K.N.L., W.L., J.M., M.K.P., J.P., J.J.S., G.M.S., D.S.W., M.P.P are current employees of Vividion Therapeutics. J.C.B., J.M.C., K.H., E.T. and T.M.K. are former employees of Vividion Therapeutics. J.D. has acted as a consultant for AstraZeneca, Jubilant, Theras, Roche, Boehringer Ingelheim and Kestrel Therapeutics and has funded research agreements with Bristol Myers Squibb, Revolution Medicines, Vividion, Novartis and AstraZeneca. M.M.A., M.I., S.R., and M.T. have no competing interests to declare.Footnotes* Corrected typos/mislabeling on Figure 2 and Figure 5E

The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency and resistance to chemo/radiotherapy. Here we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically and covalently engages C151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported C151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_C151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).

The purpose of this study was to explain relationships between neurological dysfunction, HIV serological status, and HIV risk behaviors that have not been well understood. A secondary analysis was conducted on data from 117 female prison inmates. Another 18 female inmates from the same prison were further evaluated with more specific neurological, neuropsychological, and HIV risk behavior Risk Assessment Battery (RAB) measures. Neurological function, defined by valid, reliable quantitative measures of cognition, behavior/mood, cranial nerves, motor, reflexes, and sensation, was significantly correlated with HIV RAB scores (.743, p = .006), and RAB scale scores (.824, p = .001) in HIV-negative, but not HIV-positive, inmates. Specifically, the reflex deficits subscale correlated with RAB scores (.779, p = .003) and RAB scale scores (.682, p = .015) in the HIV-negative group. These findings combined with subjects' histories suggest cerebral dysfunction possibly contributes to HIV risk behaviors in certain high-risk female inmates predating HIV infection. These findings further suggest that HIV risk reduction should target neurologically impaired females as a high-risk group. Larger studies are needed to validate these findings.