Author: Elmquist, William F. ; Zhong, Wei ; Herman, Michael G. ; Connors, Margaret A. ; Ott, Lauren L. ; Rathi, Sneha ; Bakken, Katrina K. ; Trzasko, Joshua D. ; Eckel-Passow, Jeanette E. ; Grams, Michael ; Carlson, Brett L. ; Garcia, Darwin A. ; Vaubel, Rachael A. ; Hu, Zeng ; Burgenske, Danielle M. ; Decker, Paul A. ; Remmes, Nicholas B. ; Sarkaria, Jann N.

AbstractAtaxia Telangiectasia–mutated (ATM) inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk of normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of Friend Leukemia virus B (FVB) mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose escalation to a maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose volume limits for organs at risk.

12 Sep 2024·Journal of Medicinal Chemistry

Small Molecular Inhibitors That Target ATM for Drug Discovery: Current Research and Potential Prospective

Review

Author: Wang, Yuxi ; Qian, Chunlin ; Li, Xiaoxue ; Zhang, Jifa

The protein kinase ataxia telangiectasia mutated (ATM) is a constituent of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, exerting a pivotal influence on diverse cellular processes, notably the signaling of double-strand DNA breaks (DSB) and stress response. The dysregulation of ATM is implicated in the pathogenesis of cancer and other diseases such as neurodegeneration. Hence, ATM is deemed a promising candidate for potential therapeutic interventions across a spectrum of diseases. Presently, while ATM small molecule inhibitors are not commercially available, various selective inhibitors have progressed to the clinical research phase. Specifically, AZD1390, WSD0628, SYH2051, and ZN-B-2262 are under investigation in clinical studies pertaining to glioblastoma multiforme and advanced solid tumors, respectively. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of ATM. Subsequently, we concentrate on the design concepts and structure-activity relationships (SAR) of ATM inhibitors, delineating potential avenues for the development of more efficacious ATM-targeted inhibitors.

01 Aug 2024·The Journal of Pharmacology and Experimental Therapeutics

Preclinical Systemic Pharmacokinetics, Dose Proportionality, and Central Nervous System Distribution of the ATM Inhibitor WSD0628, a Novel Radiosensitizer for the Treatment of Brain Tumors

Article

Author: Zhong, Wei ; Zhang, Wenjuan ; Le, Jiayan ; Oh, Ju-Hee ; Garcia, Darwin A ; Mladek, Ann C ; Sarkaria, Jann N ; Xue, Zhiyi ; Zhang, Wenqiu ; Elmquist, William F ; Burgenske, Danielle M ; Rathi, Sneha

Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier. The objective of this study was to evaluate the systemic pharmacokinetics and mechanisms that influence the central nervous system (CNS) distribution of WSD0628, a novel and potent ATM inhibitor, in the mouse. Further, we have used these observations to form the basis of predicting effective exposures for clinical application. We observed a greater than dose proportional increase in exposure, likely due to saturation of clearance processes. Our results show that WSD0628 is orally bioavailable and CNS penetrant, with unbound partitioning in CNS (i.e., unbound tissue partition coefficient) between 0.15 and 0.3. CNS distribution is not limited by the efflux transporters P-glycoprotein and breast cancer resistant protein. WSD0628 is distributed uniformly among different brain regions. Thus, WSD0628 has favorable pharmacokinetic properties and potential for further exploration to determine the pharmacodynamics-pharmacokinetics efficacy relationship in CNS tumors. This approach will provide critical insights for the clinical translation of WSD0628 for the treatment of primary and secondary brain tumors. SIGNIFICANCE STATEMENT: This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM inhibitor for the treatment of brain tumors. Results indicate that WSD0628 is orally bioavailable and CNS penetrant without efflux transporter liability. We also observed a greater than dose proportional increase in exposure in both the plasma and brain. These favorable pharmacokinetic properties indicate WSD0628 has potential for further exploration for use as a radiosensitizer in the treatment of brain tumors.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioma	IND Approval	United States	Wayshine Biopharm	20 Jan 2023
Central Nervous System Neoplasms	Preclinical	China	Wayshine Biopharm	-

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