This symposium draws on the experiences of academic investigators to highlight their scientific efforts and challenges in academic drug discovery. Presentations feature diverse efforts with topics ranging from the development of new platforms for targeting 'undruggable' proteins, the discovery of cyclin-kinase specific 'degraders' as tools and pharmacological interventions in cancer, the identification and pharmacologic targeting of p97 as a novel cancer target, to the development of dual-kinase inhibitors as a polypharmacologic strategy for overcoming adaptive resistance to therapy in acute myeloid leukemia.