Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia.

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

Homeorhesis: envisaging the logic of life trajectories in molecular research on trauma and its effects.

What sets someone on a life trajectory? This question is at the heart of studies of 21st-century neurosciences that build on scientific models developed over the last 150 years that attempt to link psychopathology risk and human development. Historically, this research has documented persistent effects of singular, negative life experiences on people's subsequent development. More recently, studies have documented neuromolecular effects of early life adversity on life trajectories, resulting in models that frame lives as disproportionately affected by early negative experiences. This view is dominant, despite little evidence of the stability of the presumably early-developed molecular traits and their potential effects on phenotypes. We argue that in the context of gaps in knowledge and the need for scientists to reason across molecular and phenotypic scales, as well as time spans that can extend beyond an individual's life, specific interpretative frameworks shape the ways in which individual scientific findings are assessed. In the process, scientific reasoning oscillates between understandings of cellular homeostasis and organisms' homeorhesis, or life trajectory. Biologist and historian François Jacob described this framework as the "attitude" that researchers bring to bear on their "objects" of study. Through an analysis of, first, historical and contemporary scientific literature and then ethnographic research with neuroscientists, we consider how early life trauma came to be associated with specific psychological and neurobiological effects grounded in understandings of life trajectories. We conclude with a consideration of the conceptual, ontological, and ethical implications of interpreting life trajectories as the result of the persistence of long-embodied biological traits, persistent life environments, or both.

Troubling Neurobiological Vulnerability: Psychiatric Risk and the Adverse Milieu in Environmental Epigenetics Research.

In post-genomic science, the development of etiological models of neurobiological vulnerability to psychiatric risk has expanded exponentially in recent decades, particularly since the neuromolecular and biosocial turns in basic research. Among this research is that of McGill Group for Suicide Studies (MGSS) whose work centers on the identification of major risk factors and epigenetic traits that help to identify a specific profile of vulnerability to psychiatric conditions (e.g., depression) and predict high-risk behaviors (e.g., suicidality). Although the MGSS has attracted attention for its environmental epigenetic models of suicide risk over the years and the translation of findings from rodent studies into human populations, its overall agenda includes multiple research axes, ranging from retrospective studies to clinical and epidemiological research. Common to these research axes is a concern with the long-term effects of adverse experiences on maladaptive trajectories and negative mental health outcomes. As these findings converge with post-genomic understandings of health and also translate into new orientations in global public health, our article queries the ways in which neurobiological vulnerability is traced, measured, and profiled in environmental epigenetics and in the MGSS research. Inspired by the philosophy of Georges Canguilhem and by literature from the social studies of risk and critical public health, we explore how the epigenetic models of neurobiological vulnerability tie into a particular way of thinking about the normal, the pathological, and the milieu in terms of risk. Through this exploration, we examine how early life adversity (ELA) and neurobiological vulnerability are localized and materialized in those emerging models while also considering their broader conceptual and translational implications in the contexts of mental health and global public health interventions. In particular, we consider how narratives of maladaptive trajectories and vulnerable selves who are at risk of harm might stand in as a "new pathological" with healthy trajectories and resilient selves being potentially equated with a "new normal" way of living in the face of adversity. By troubling neurobiological vulnerability as a universal biosocial condition, we suggest that an ecosocial perspective may help us to think differently about the dynamics of mental health and distress in the adverse milieu.

Shared Relations: Trauma and Kinship in the Afterlife of Death.

Since 2013, we have studied the logic and narratives of an environmental epigenetics research team that studies the correlations between early childhood adversity (ECA), specific biomarkers, and suicide risk. Within this research program, kin of the deceased participate in psychological autopsies, which researchers use to establish to classify the deceased within a typology of suicide with or without abuse. We focus on the words of these family respondents and their reflections on the life and death of their loved ones, and life after that death, to consider the slippery, transgressive, and relational character of trauma and its effects. Studies of the residues of past experiences provide crucial insights into the complex, unpredictable, and unsettled nature of kin relations. These relations are based in entwined biographies of the living and the dead and illustrate the holds that people have on each other and destabilize biomedical models of individualized trajectories of suicide risk. [suicide, psychological autopsies, trauma, care, kinship].

Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity.

Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.

Time, trauma, and the brain: How suicide came to have no significant precipitating event.

In this article, we trace shifting narratives of trauma within psychiatric, neuroscience, and environmental epigenetics research. We argue that two contemporary narratives of trauma - each of which concerns questions of time and psychopathology, of the past invading the present - had to be stabilized in order for environmental epigenetics models of suicide risk to be posited. Through an examination of these narratives, we consider how early trauma came to be understood as playing an etiologically significant role in the development of suicide risk. Suicide, in these models, has come to be seen as a behavior that has no significant precipitating event, but rather an exceptional precipitating neurochemical state, whose origins are identified in experiences of early traumatic events. We suggest that this is a part of a broader move within contemporary neurosciences and biopsychiatry to see life as post: seeing life as specific form of post-traumatic subjectivity.

Electrolytic macrocyclizations: scalable synthesis of a diazonamide-based drug development candidate.

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic.

Highly regioselective intermolecular arylation of 1,2,3,4-tetrahydropyridines.

Using a catalytic amount of PdCl2(dppf) x CH2Cl2 in combination with Ag3PO4 and NaOAc, a range of arylated 1,2,3,4-tetrahydropyridines are synthesized in good yields and with complete selectivity at the beta-position. The reaction is compatible with a variety of electron-donating and electron-withdrawing aryl iodides as well as with heteroaryl iodides. The application of these tetrahydropyridines toward the synthesis of polysubstituted piperidines is also demonstrated.

Palladium-catalyzed benzylic C-H insertion of 2-substituted N-iminopyridinium ylides.

Palladium-catalyzed direct benzylic C-H arylation of 2-alkyl substituted N-iminopyridinium ylides is described. The insertion can be conducted with several electron-poor and electron-rich aryl chlorides in good yields. This work adds to the few examples of sp3 C-H insertions that have been reported so far.

Palladium-catalyzed direct C-h arylation of N-iminopyridinium ylides: application to the synthesis of (+/-)-anabasine.

Palladium-catalyzed direct C-H arylation of N-iminopyridinium ylides provides a powerful and versatile method for the synthesis of functionalized piperidines in good yields. Chemoselective functionalization of the pyridinium ring in the presence of a pyridine substituent is possible as exemplified by the expedient synthesis of anabasine in 61% overall yield over three steps.

New methodology toward chiral, non-racemic 2,5-cis-substituted piperidines via Suzuki cross-coupling.

1,2,3,4-Tetrahydropyridines were halogenated upon treatment with iodine to obtain the desired cross-coupling precursors. Diastereoselective hydrogenation of Suzuki cross-coupling adducts allowed the facile asymmetric synthesis of 2,5-cis-substituted piperidines in five steps from readily available pyridine.