Research

The Hinshaw Lab studies the molecular mechanisms of cell division and leverages this knowledge to develop new therapeutic strategies for cancer. We combine cryo-electron microscopy, chemical biology, and genetics to understand and reprogram the protein machines that govern chromosome segregation and cell fate.

Cell Division

We are searching for the biochemical logic that drives high-fidelity chromosome segregation during mitosis. This deceptively simple process depends upon an astonishingly complex system of interlocking regulatory and structural modules. The molecular components of many of these modules are known, and we are only now beginning to understand how they are assembled, regulated, and coordinated in space and time.

Recent advances in cryo-electron microscopy, combined with new chemical biology and genetic tools, have generated enormous momentum in this area. Among the many open questions, we are especially interested in defining the mechanistic bases of positive and negative regulation at the kinetochore, and in understanding how these activities restrict stable microtubule attachment to a single locus on each human chromosome.

These are fundamentally important problems with direct implications for chromosome instability in cancer, for the mechanisms of common chemotherapies, and for the development of new therapeutic strategies that selectively induce or disrupt aberrant mitosis in tumor cells.

Drug Discovery: New Therapeutic Mechanisms

We use structural biology as a foundation for discovering and developing new targeted cancer therapeutics. Our work focuses on small molecules that elicit powerful biochemical responses by activating signaling pathways that are dormant or disabled in cancer cells.

Recent examples include:

(i) molecular glues that hijack innate immune signaling to induce degradation of nuclear pore complex components in cancer cells;

(ii) bifunctional small molecules that activate programmed cell death pathways in diffuse large B cell lymphoma (DLBCL); and

(iii) compounds that convert cancer-associated DNA damage into a strong, irreversible cell death signal, with excellent therapeutic indices in murine models of small cell lung cancer (SCLC).