Schreiber Lab Major Areas of Research

I. Next-generation synthesis

In the first step of research in the Schreiber group, before biological studies are undertaken, group members use diversity-oriented synthesis (DOS) to yield performance-diverse small-molecule screening collections that enable the discovery of small molecules that modulate nearly any aspect of human biology. Due to their stereochemically and skeletally diverse structures, these compounds collectively provide valuable structure–activity relationships, including those derived from stereochemistry. The compounds are made using short, modular pathways and have features that facilitate their optimization in follow-up biological investigations. In parallel, the compounds are made using novel synthetic strategies that attach bar codes so that they can be affinity purified using disease-relevant proteins.

Powerful methods for determining mechanisms of action are being developed; for example, by measuring the binding of small molecules to proteins in cells. Real-time annotations of compounds prepared using DOS are achieved using novel multiplexed methods such as cell painting and HiTSeq.

II. Cancer therapeutics that overcome resistance

Overcoming resistance to cancer therapy has emerged as one of the most pressing and universal issues in oncology. Targeted therapies, including ones being developed in the Schreiber lab to treat chordoma cancers, and immunotherapies are two of the most transformative and promising advances in cancer treatment over the last two decades. Yet they, like conventional chemotherapies, frequently succumb to the ability of cancers eventually to resist therapeutic attacks on their vulnerabilities, reversing the initially impressive clinical responses to these treatments. To exploit genetic or immunological cancer dependencies safely, effectively, and durably, and to extend the use of chemotherapy, group members are learning how to avoid or overcome resistance specifically by discovering common (frequently encountered) therapy-resistant cell states (e.g., apoptosis-resistant state), and to target their dependencies.

Using the Cancer Therapeutics Response Portal (CTRP), group members have discovered one such common, non-mutational therapy-resistant state by correlating cancer cell gene-expression signatures with small-molecule sensitivity. This state is associated with mesenchymal characteristics of cancer cells, and indeed this state also appears to be associated with certain sarcomas – cancers in tissues of mesenchymal or mesonephric origin. Importantly, this state emerges by non-mutational mechanisms from treatment with either chemotherapy or targeted therapeutics across several cancer types. This common therapy-resistant state was found to have underlying vulnerabilities that can be attacked by specific therapeutic agents. Group members uncovered small molecules that target different enzymes in this pathway and observed promising results – for example, killing ‘persister’ cancer cells selectively and potently.

III. Microbial therapeutics with novel mechanisms of action

Compounds derived from DOS have yielded many probes of mammalian cell circuitry, but they have also yielded novel compounds that modulate essential targets in pathogens including Mycobacterium tuberculosis, gram-negative bacteria, and causal agents in leishmaniasis and Chagas Disease, among others. Group members have recently uncovered promising antimalarial agents that target each of the key stages of the life cycle of Plasmodium falciparum, the pathogen that cause malaria.

Group members identified DOS-derived compounds having novel mechanisms of action (data have been made available at the Malaria Therapeutics Response Portal (MTRP), including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. The bicylic azetidines display single low-dose cure with activity against all parasite life stages in multiple in vivo efficacy models. These findings identify bicyclic azetidines with the potential to cure and prevent transmission of the disease as well as protect populations at risk, all in a single oral exposure, and highlight the strength of DOS to reveal promising therapeutic targets.

IV. Therapeutics having novel mechanisms of action for the treatment of genetic prion disease and Alzheimer’s Disease

Prion diseases are fatal neurodegenerative diseases that arise when the prion protein (PrP), a protein normally present in the brain, misfolds into a toxic and infectious form. Evidence from human genetics and animal models indicates that either stabilizing PrP in its normal form, or reducing the amount of PrP in the brain, would be safe and effective strategies for treating prion disease. PrP prion diseases such as Creutzfeldt-Jakob disease are caused by the templated misfolding of the cellular prion protein, PrP^C, into a disease-causing conformation referred to as the scrapie prion protein, or PrP^Sc. Small molecules that cause the depletion or stabilization of PrP^C may block prion replication and prevent disease. Schreiber group members including patient-turned-scientist duo Sonia Vallabh and Eric Minikel are searching for molecules capable of stabilizing or reducing PrP, with the goal of developing therapeutic leads towards treating prion disease. 

Apolipoprotein E (apoE) is the predominant apolipoprotein in the brain, where it forms particles similar to high-density lipoproteins (HDL) and plays a prominent historical role as the most potent risk gene for late-onset Alzheimer’s disease (LOAD). The three common isoforms of apoE (apoE2, apoE3, and apoE4) differ from each other by their cysteine/arginine content at two polymorphic sites. The risk for LOAD increases 3-fold with one copy and over 10-fold with two copies of apoE4 relative to the risk associated with the common apoE3 allele, while the cysteine-containing apoE2 is protective. The precise molecular mechanism(s) by which apoE modifies LOAD risk remain unresolved. However, human genetics points to additional cysteine/arginine variants in apolipoproteins that may reveal a common pathophysiology. Apolipoprotein A-I (apoA-I) is the major protein constituent of HDL in plasma. The Milano variant of apoA-I, apoA-I_M, features an Arg173Cys mutation that is protective against cardiovascular disease, and administration of recombinant apoA-I_M results in regression of atherosclerosis in patients with acute coronary syndromes. The Paris variant of apoA-I contains an Arg151Cys substitution and appears to phenocopy the vascular disease protection observed in the Milano variant. Thus, genetic evidence suggests that cysteine mutations at key sites confer disease-protective properties to HDL-forming apolipoproteins. 

Schreiber group members have discovered a property of these genetic alterations not previously known. Learning from these experiments of nature, a blueprint has emerged that is guiding the search for new treatments of apoliporotein-associated disease including LOAD.