Macrocyclization can enhance the selectivity of acyclic compounds toward structurally similar biological targets such as kinases. WEE1 regulates cellular homeostasis and is a promising target in oncology. The clinical candidate AZD1775 (1) failed to progress past Phase II trials because of patient tolerability issues, likely due to off-target inhibition of polo-like kinase 1 (PLK1). Herein, a computer-aided drug design approach was conducted to develop a macrocycle based on the 1-WEE1 X-ray cocrystal structure. Significantly enhanced WEE1 inhibitory selectivity over PLK1 was determined for leading macrocycle 2, which also demonstrated broader kinome-wide selectivity. Patient-derived organoids from colorectal cancer (CRC) peritoneal and liver metastases, treated with 2, demonstrated comparably strong or enhanced anticancer efficacy compared to that of 1. Against patient-matched normal colon vs primary CRC organoids, 2 potently and selectively treated CRC, as well as enhanced DNA damage compared to 1. Finally, the X-ray cocrystal structure of 2 bound to WEE1 validated its computationally predicted bioactive binding mode.
Joel L Syphers, Josephine A. Wright, Adarsh Kumar et al.· Journal of Medicinal Chemist...· 0 citations
The nervous system has emerged as a critical regulator of cancer progression. Recent studies demonstrate that peripheral neurons shape tumor growth, dissemination, and therapeutic response by regulating multiple components of the tumor microenvironment. In parallel, tumors within the body remodel their neural niche by recruiting innervation and modulating neuronal phenotype and activity. This bidirectional cross talk positions neural circuits as integral components of the tumor ecosystem, linking environmental cues, including metabolic stress, inflammation, and the impact of treatment, to coordinated multicellular responses that promote progression and treatment resistance. Here, we review the field of cancer neuroscience with a focus on solid tumors originating outside the central nervous system. We synthesize mechanistic insights into how the peripheral nervous system shapes the tumor microenvironment to influence tumor behavior and highlight emerging therapeutic opportunities to target neural pathways. Together, these findings identify the nervous system as an upstream regulator of cancer biology and a tractable target for intervention.
Aeson Chang, Shenghong Zhu, Terrance Lam et al.· Journal of Experimental Medi...· 0 citations
