Discovery of Potent and Selective Covalent Inhibitors of HER2WT and HER2YVMA.

HER2 overexpression and amplification have been identified as oncogenic drivers, and the development of therapies to treat tumors harboring these markers has received considerable attention. Activation of HER2 signaling and subsequent cell growth can also be induced by HER2 mutations, including the common YVMA insertion in exon 20 within the kinase domain. Enhertu is currently the only approved treatment for HER2 mutant tumors in NSCLC. TKIs tested in this space have suffered from off-target activity, primarily due to EGFRWT inhibition or attenuated activity against HER2 mutants. The goal of this work was to identify a TKI that would provide robust inhibition of oncogenic HER2WT and HER2 mutants while sparing EGFRWT activity. Herein, we describe the development of a potent, covalent inhibitor of HER2WT and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFRWT.

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.

8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors.

A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aß1-40 at 60 mg/kg (PO).

Discovery of 7-tetrahydropyran-2-yl chromans: ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid ß-protein (Aß) in the central nervous system.

In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2' sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aß1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (Cfree,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aß1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.

Chronic posttraumatic stress disorder after facial injury: a 1-year prospective cohort study.

BACKGROUND: This study examined the prevalence, severity, and predictors of persistent traumatic stress symptoms in socioeconomically disadvantaged adults after orofacial injury. METHODS: A 1-year prospective study of 336 socioeconomically disadvantaged adults treated for orofacial injury at a Level I trauma center was conducted. Univariate analyses were performed on early measures of injury characteristics, prior trauma exposure, coping resources, and psychosocial functioning to select potential predictors of 1-year posttraumatic stress disorder (PTSD) scores; independence of variable contribution was then evaluated in multiple regression analyses. RESULTS: A substantial number of patients (23%) continued to experience significant PTSD symptomatology at 12 months. Predictors of PTSD symptoms at 12 months included current and lifetime mental health and social service needs, lifetime social service use, prior trauma exposure, sum of stressful life events in the year preceding injury, patient report of pain severity and inadequate social support at 10 days postdischarge, and PTSD scores at 1 month. One-month PTSD symptoms, unmet social service need, and need for more instrumental and emotional support were independent predictors of 12-month PTSD outcomes. Limitations include loss to follow up, use of self-report measures, and the possibility of additional traumatization in the follow-up year influencing symptom levels. CONCLUSIONS: Many socioeconomically disadvantaged adults manifest negative psychological outcomes even 1 year after an orofacial injury. Poor social support and unmet social service needs immediately after the injury, as well as high PTSD symptoms at 1 month postinjury, are strongly associated with the risk of developing chronic PTSD. The surgical management of orofacial injuries in disadvantaged individuals should integrate case management that addresses psychosocial sequelae and patient service needs.

The development of acute post-traumatic stress disorder after orofacial injury: a prospective study in a large urban hospital.

PURPOSE: Psychologic distress is a common outcome among trauma survivors. This report examines both the development and predictors of acute post-traumatic stress disorder (PTSD) symptoms in a sample of US inner-city orofacial trauma survivors seeking treatment in a publicly funded hospital. PATIENTS AND METHODS: Baseline data were collected from 336 patients seeking urgent care for an oral injury (mandibular or midfacial fracture). Participants were predominantly unemployed, unmarried, African American or Hispanic men in their 30s. One-month follow-up assessments of PTSD symptoms were conducted on the available 84% of the sample. RESULTS: Absolute levels of PTSD symptoms were high at 1 month; 25% of the sample appeared to meet diagnostic criteria for acute PTSD, based on a self-report of symptoms. Variables associated with self-reports of higher rates of PTSD symptoms included older age, being female, prior psychologic disturbance as reflected in lifetime and current mental health and social service need and use, exposure to and distress at a prior trauma as well as overall high rates of stressful life events in the past year, injury pain, psychologic distress at hospital discharge, and unmet social support needs during the recovery phase. CONCLUSIONS: A substantial subsample of these traumatized medical patients had negative psychologic outcomes at 1 month. Results underscore the potential use of screening survivors of orofacial injury at urban trauma centers for PTSD and developing systems of care that facilitate referral to appropriate psychologic treatment.

Psychosocial sequelae and correlates of orofacial injury.

Orofacial injury is a condition that disproportionately affects disadvantaged minorities--particularly young men--with great personal and health care consequences. Beyond the overt physical injury, a large proportion of the presenting patients manifest acute psychological sequelae. Although many patients may recover, in a sizeable proportion the symptoms may persist for extended periods of time and prove to be an obstacle to rehabilitation and reintegration. Health care givers should pay equal attention to evolving psychological sequelae of facial injuries. Strategic questions and screening for risk indicators can help with timely posttrauma identification of individuals most vulnerable to the development of acute and chronic symptomatology.