Brett Bookser

Principal Research Analyst

Brett is a Principal Research Analyst, Drug Discovery for Drug Hunter. He has spent more than half of his life hunting drugs for biotechs and academic groups for diseases including cancer, infections, cystic fibrosis, CNS, metabolic, cardiovascular, and others. Starting from a sesquiterpene total synthesis organic chemistry PhD and a physical organic chemistry postdoc, he gained an early appreciation for how molecules are synthesized, and what they look like in 3D and physical property space. Brett is attracted to unusual structural motifs in drug molecules and understanding what drove chemists to use them. He is also on the lookout for small and subtle structural changes that greatly affect assay performance. Another area of curiosity is tissue specificity as a way of avoiding toxicity. Finally, Brett feels we are in a special new golden age of drug discovery with many new platforms and strategies for important disease targets. At Drug Hunter, he can dive deep into these interests and deliver insights to the community to speed drug discovery. In his free time, Brett takes long walks into cool Berkeley Hills neighborhoods with Biscuit, his indefatigable canine companion.

HRX-215

HRX-215 is an orally bioavailable MKK4 inhibitor for liver regeneration. In just over a decade since they discovered the dual specific kinase MKK4 as a master regulator of hepatocyte regeneration, HRX-215 completed a FIH clinical trial. This article is a fascinating case study on harnessing the liver's natural regenerative capacity, identifying key regulators of liver regeneration, and leveraging a kinase inhibitor with reported off-target activity for MKK4 as a suitable starting point, among other insights.

Molecule

AZ-PRMT5i-1

AZ-PRMT5i-1 is an orally bioavailable MTA-cooperative PRMT5 inhibitor that specifically targets MTAP-deleted cancers and is structurally related to AZ’s clinical candidate, AZ3470. This case study is an excellent example of utilizing bioisosteric replacements for polar guanidine headgroups, rigidifying scaffolds through spirocyclization to reduce rotatable bonds, and leveraging fluorine atoms beyond simply blocking metabolic soft spots.

Molecule

revumenib

Revumenib (Revuforj®) is approved by the FDA as an oral, first-in-class menin-MLL interaction inhibitor for acute leukemia (AL). Since inhibition of the menin-MLL fusion protein interaction is selective for AL with a KMT2A translocation, it does not compromise normal hematopoietic function. This article covers the background, optimization and clinical development that has led to the approval of this groundbreaking new drug in a hard-to-treat indication.

Molecule

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