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Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies

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Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies pharmaceuticals Article Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies Jiawang Liu 1,2,†, Nirmal Rajasekaran 3,† , Ahamed Hossain 1, Changde Zhang 1 , Shanchun Guo 1, Borui Kang 1, Hunsoon Jung 3, Hongjoong Kim 3,* and Guangdi Wang 1,4,* 1 RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA; [email protected] (J.L.); [email protected] (A.H.); [email protected] (C.Z.); [email protected] (S.G.); [email protected] (B.K.) 2 College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA 3 Enhancedbio Inc., 19 Sangwon-gil, Seongdong-gu, Seoul 04779, Korea; [email protected] (N.R.); [email protected] (H.J.) 4 Zenopharm Inc., 1441 Canal Street, New Orleans, LA 70112, USA * Correspondence: [email protected] (H.K.); [email protected] (G.W.) † These authors contributed equally to this work. Abstract: Fulvestrant-3-boronic acid (ZB716), an oral selective estrogen receptor degrader (SERD) under clinical development, has been investigated in ADME studies to characterize its absorption, metabolism, and pharmacokinetics. ZB716 was found to have high plasma protein binding in human and animal plasma, and low intestinal mucosal permeability. ZB716 had high clearance in hepatocytes of all species tested. ZB716 was metabolized primarily by CYP2D6 and CYP3A. In Citation: Liu, J.; Rajasekaran, N.; human liver microsomes, ZB716 demonstrated relatively low inhibition of CYP1A2, 2C8, 2C9, 2C19, Hossain, A.; Zhang, C.; Guo, S.; Kang, 2D6, and 3A4 (when testosterone was used as the substrate), and no inhibition of CYP2B6 and 3A4 B.; Jung, H.; Kim, H.; Wang, G. (when midazolam was used as the substrate). In assays for enzyme activity, ZB716 induced CYP1A2, Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability 2B6, and 3A4 in a concentration-dependent manner. Single-dose and repeated-dose pharmacokinetic and Favorable Pharmacokinetic studies in rats and dogs showed oral bioavailability, dose-proportional drug exposure, and drug Profile in Preclinical ADME Studies. accumulation as measured by maximum concentration and area under the concentration–time curve Pharmaceuticals 2021, 14, 719. (AUC). https://doi.org/10.3390/ph14080719 Keywords: selective estrogen receptor degrader; ZB716; pharmacokinetics; oral bioavailability; breast Academic Editor: Abdelwahab Omri cancer; fulvestrant Received: 28 June 2021 Accepted: 22 July 2021 Published: 26 July 2021 1. Introduction Fulvestrant was approved for second-line endocrine treatment in 2002 [1], and recently Publisher’s Note: MDPI stays neutral as a first-line therapy for advanced or metastatic estrogen receptor-positive (ER+), human with regard to jurisdictional claims in epidermal growth factor receptor 2-negative (HER2-) breast cancer [2,3]. Fulvestrant acts as published maps and institutional affil- a full estrogen receptor (ER) antagonist that degrades the receptor protein, conferring clini- iations. cal efficacy in treating patients with progressive disease while on tamoxifen or aromatase inhibitors. However, fulvestrant is not orally bioavailable, and its poor pharmacokinetic properties and insufficient drug exposure are believed to limit clinical response, which could be further improved. Efforts to increase fulvestrant exposure through multiple clini- Copyright: © 2021 by the authors. cal trials between 2005 and 2009 led to subsequent approval of a higher dosage regimen Licensee MDPI, Basel, Switzerland. in 2010 [4]. Still, clinical studies indicate that at the maximum injectable limit of 500 mg, This article is an open access article the therapeutic effect has not reached its optimal level [5]. This unmet clinical need has distributed under the terms and driven the continued search for an ER-degrading antiestrogen that could achieve greater conditions of the Creative Commons drug exposure through high potency and oral bioavailability. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ In the past 10 years, over 13 oral SERDs have entered clinical trials to test their safety 4.0/). and efficacy in ER+ breast cancer patients [6]. These oral SERDs are nonsteroidal small Pharmaceuticals 2021, 14, 719. https://doi.org/10.3390/ph14080719 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 16 Pharmaceuticals 2021, 14, 719 In the past 10 years, over 13 oral SERDs have entered clinical trials to test their 2safety of 16 and efficacy in ER+ breast cancer patients [6]. These oral SERDs are nonsteroidal small molecules characterized by an ER-binding motif and a side chain featuring either an moleculesacrylic acid characterized or an amino by base an ER-bindinggroup that confer motif andantiestrogenic a side chain and featuring ER-degrading either an activities acrylic acid[7]. In or preclinical an amino base studies group evaluating that confer efficacy antiestrogenic and mode and of action, ER-degrading the oral SERD activities candidates [7]. In preclinicalare compared studies with evaluating the benchmark efficacy fulvestrant—the and mode of action, only theclinically oral SERD approved candidates SERD. are In comparedmost cases, with the theoral benchmark SERDs are fulvestrant—thefound to be comparable, only clinically but not approved superior, to SERD. fulvestrant In most in cases,ER binding, the oral ER SERDs degradation, are found tissue to be selectivity, comparable, and but inhibiting not superior, xenograft to fulvestrant tumor growth. in ER It binding,is hoped ER that degradation, the oral SERDs, tissue when selectivity, given andto patients, inhibiting would xenograft derive tumor greater growth. efficacy It via is hopedhigher that drug the exposure oral SERDs, than when fulvestrant. given to patients, would derive greater efficacy via higher drug exposureThe main than challenge fulvestrant. that oral SERDs seek to overcome, therefore, is the pharmacoki- neticThe limitations main challenge of fulvestrant, that oral but SERDs not its seekpotency to overcome, as a pure antiestr therefore,ogen is theand pharmacoki- ER degrader. neticIf fulvestrant limitations were of fulvestrant, orally bioavailable but not its and potency the level as aof pure drug antiestrogen exposure could and ER be degrader.increased Ifby fulvestrant oral dosage, were its orallyclinical bioavailable efficacy could and be the conceivably level of drug enhanced exposure significantly. could be increased In reality, byglucuronidation oral dosage, its of clinical fulvestrant efficacy by could UDP-gl be conceivablyucuronosyltransferase enhanced significantly. (UGT) enzymes In reality, ex- glucuronidationpressed in both ofthe fulvestrant intestine byand UDP-glucuronosyltransferase liver may effectively inactivate (UGT) and enzymes eliminate expressed the drug inbefore both theit reaches intestine systemic and liver circulation may effectively [8–10]. inactivateTo circumvent and eliminatethe first pass the drug clearance before that it reacheslimits fulvestrant’s systemic circulation oral absorption, [8–10]. To we circumvent implemented the first a solution pass clearance where the that 3-OH limits group fulves- of trant’sfulvestrant oral absorption, is replaced we by implemented a boronic aacid solution group where to obtain the 3-OH fulvestrant-3-boronic group of fulvestrant acid is replaced(ZB716) by(Figure a boronic 1) [11]. acid The group rationale to obtain for fulvestrant-3-boronicthis chemical modification acid (ZB716) was based (Figure on1 our)[ 11 re-]. Thesearch rationale findings for [12–15], this chemical where modificationboronic bioiso wassteres based can onsignificantly our research reduce findings the first-pass [12–15], wheremetabolism boronic of bioisosteres phenolic compounds. can significantly Our studies reduce confirmed the first-pass that metabolism ZB716 retains of phenolicfull bind- compounds.ing affinity of Our the studies steroidal confirmed moiety thatof fulv ZB716estrant, retains while full minimizing binding affinity glucuronidation of the steroidal and moietysulfation of fulvestrant,[11–13]. We while found minimizing that ZB716glucuronidation acted as a pure andantiestrogen sulfation and [11– ER13]. degrader We found in thatER+ ZB716 breast acted cancer as cells, a pure and antiestrogen potently inhibited and ER degradertumor growth in ER+ in breastclinically cancer relevant cells, xeno- and potentlygraft breast inhibited cancer tumor models growth [12]. in clinically relevant xenograft breast cancer models [12]. FigureFigure 1. 1.Structure Structure of of fulvestrant fulvestrant and and ZB716. ZB716. WeWe report report preclinical preclinical studies studies in in support support of of the the investigational investigational new new drug drug (IND) (IND) applica- appli- tioncation for afor phase a phase 1 clinical 1 clinical trial trial of ZB716. of ZB716. These These studies studies include includein vitro in vitroADME ADME investigations, investiga- andtions, pharmacokinetic and pharmacokinetic (PK) and (PK) toxicokinetic and toxicoki (TK)netic studies (TK) instudies rodents in androdents dogs. and The dogs. species The andspecies strains and used strains in the used present in the studies present reflected studies those reflected employed those employed in the toxicological in the toxicolog- testing ofical ZB716, testing in of order ZB716, to enable in order meaningful to enable assessmentmeaningful of assessment the exposure of the levels exposure in the toxicitylevels
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