Paul C. Trippier

University of Nebraska Medical Center

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T.M. Penning

University of Pennsylvania

Kshitij Verma

Texas Tech University Health Sciences Center

Tianzhu Zang

Enanta Pharmaceuticals (United States)

Nehal Gupta

Texas Tech University Health Sciences Center

Phumvadee Wangtrakluldee

Translational Therapeutics (United States)

Sravan K. Jonnalagadda

University of Nebraska Medical Center

Bader Huwaimel

University of Ha'il

Nihar Kinarivala

Memorial Sloan Kettering Cancer Center

Thomas J. Abbruscato

Texas Tech University Health Sciences Center

Shirisha Jonnalagadda

Nebraska Medical Center

Cooperative Institutions

University of Nebraska Medical Center

197

Hudson Institute

148

Texas Tech University

117

Texas Tech University Health Sciences Center

108

John Wiley & Sons (United States)

Institut de l'Information Scientifique et Technique

University of Maryland, Baltimore

Nebraska Medical Center

Tel Aviv University

University of Ljubljana

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CCDC 2204985: Experimental Crystal Structure Determination

The Cambridge Structural Database (2023)

Siavash Shahbazi Nia M. Anwar Hossain Guangchen Ji Sravan K. Jonnalagadda Samuel Obeng

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc2d0gkg

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Reversal of Apalutamide and Darolutamide Aldo-Keto Reductase 1C3-Mediated Resistance by a Small Molecule Inhibitor

ACS Chemical Biology (2020)

Ahmed Morsy Paul C. Trippier

The antiandrogen therapeutics apalutamide and darolutamide entered the clinic in 2018 and 2019, respectively, for the treatment of castration-resistant prostate cancer (CRPC). Increased expression of the enzyme aldo-keto reductase 1C3 (AKR1C3) is phenotypic of CRPC. The enzyme acts to circumvent castration by producing potent androgens that drive proliferation. Furthermore, AKR1C3 mediates chemotherapeutic resistance to the standard of care, enzalutamide, a structural analogue of apalutamide. Resistance develops in almost all CRPC patients within three months of beginning treatment. Herein, we report that both apalutamide and the structurally distinct darolutamide induce AKR1C3 expression in in vitro models of prostate cancer and are susceptible to AKR1C3-mediated resistance. This effect is countered by pretreatment with a potent and highly selective AKR1C3 inhibitor, sensitizing high AKR1C3 expressing prostate cancer cell lines to the action of both chemotherapeutics with a concomitant reduction in expression of AKR1C3 and the biomarker prostate-specific antigen.

Enzalutamide

Aldo-keto reductase

10.1021/acschembio.0c00069

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Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer

European Journal of Medicinal Chemistry (2020)

Md Ashraf-Uz-Zaman Sadisna Shahi Racheal G. Akwii Md Sanaullah Sajib Mohammad Jodeiri Farshbaf

Triple-negative breast cancer

10.1016/j.ejmech.2020.112866

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Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands

European Journal of Medicinal Chemistry (2023)

Siavash Shahbazi Nia Mohammad Anwar Hossain Guangchen Ji Sravan K. Jonnalagadda Samuel Obeng

Lipophilicity

10.1016/j.ejmech.2023.115309

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Development of A Novel RON Targeted Antibody‐Drug Conjugates using Cysteine Bridging Technology for Potential Treatment of Pancreatic Cancer

The FASEB Journal (2018)

Sreedhar Reddy Suthe Hang‐Ping Yao Paul C. Trippier Ming‐Hai Wang

Therapeutics targeting known oncoproteins have been applied for pancreatic cancer treatment but clinical outcomes are not promising. Hence, there is an urgent need to identify novel targets and develop effective drugs to improve pancreatic cancer therapeutic index. Antibody‐drug conjugates (ADC) represent a promising class of drugs for targeted cancer therapy. Here we developed a novel ADC targeting RON receptor tyrosine kinase for potential pancreatic cancer treatment. To this end, we have synthesized a bis‐alkylating linker (BL), attached to a lysosomal protease‐cleavable dipeptide with payload Monomethyl auristatin E (MMAE). The BL‐MMAE was then conjugated to Zt/g4 (anti‐RON mAb) through cysteine bridging technology to produce Zt/g4‐BL‐MMAE with a relatively homogeneous conjugation profile and an antibody to drug ratio of 1:4. Zt/g4‐BL‐MMAE showed significant improvement in drug conjugation homogeneity and serum stability over conventional ADCs prepared by maleimide‐based linkers. In pancreatic cancer cell lines overexpressing RON, Zt/g4‐BL‐MMAE specifically targeted RON‐expressing tumor cells and was effective in rapid induction of cell surface RON endocytosis. Functional analysis revealed that Zt/g4‐BL‐MMAE caused cell cycle arrest at G2/M phase, reduction of cell viability and subsequently resulted in massive cell death. The calculated IC50 is in the range of 1 to 2 μg/ml. Therapeutic studies using mouse xenograft models are currently underway to determine the efficacy of Zt/g4‐BL‐MMAE for pancreatic and other epithelial cancers. We conclude that Zt/g4‐BL‐MMAE is a novel anti‐RON ADC with excellent conjugation profile, serum stability, and selective cytotoxicity for pancreatic cancer cells. This work provides a pharmaceutical opportunity for evaluating potentials of RON‐targeted ADCs in pancreatic cancer treatment in the future. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Antibody-drug conjugate

Conjugate

Therapeutic index

10.1096/fasebj.2018.32.1_supplement.807.7

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Expedient Single Step Access to Strained Tricyclic Ketals

Sravan K. Jonnalagadda Bader Huwaimel Shirisha Jonnalagadda Jered C. Garrison Paul C. Trippier

The synthesis of cyclopropyl methyl ketones and highly strained fused substituted dihydrobenzopyran cyclopropyl lactones derived from coumarin carboxylates and chloroacetone in the presence of potassium carbonate is reported. One step synthetic access to the previously unknown dihydrobenzopyran cyclopropyl tricyclic ketals is achieved with wide substrate scope. Substituted coumarin carboxylates, phenylamides or a quinolin-2(1H)-one possessing alkyl electron donating (methyl, t-butyl) and electron withdrawing groups (F, Cl, Br, NO2) in the 4 or 6 positions formed the highly strained dihydrobenzopyran cyclopropyl tricyclic ketals in moderate yield alongside the expected coumarin carboxylate. Saturation or substitution at the 5-position or 6-OMe afforded no tricyclic ketal compound but solely coumarin carboxylates. The formation of both structures in selected derivatives was confirmed by X-ray crystallography. A plausible mechanism is proposed for the formation of the fused lactone; via intramolecular rearrangement of cis cyclopropyl methyl ketones with phenolic acetate via the formation of a hemiacetal.

Tricyclic

Hemiacetal

Potassium carbonate

10.33774/chemrxiv-2021-574sw

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Figure S3 from AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

Kshitij Verma Nehal Gupta Tianzhu Zang Phumvadee Wangtrakluldee Sanjay Srivastava

<p>Supplementary figure S3: Metabolic instability of (A) Baccharin and (B) ester derivative KV-32 on incubation with mouse S9 fractions.</p>

Enzalutamide

10.1158/1535-7163.22506684

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Editorial (Thematic Issue: Small Molecule Drug Discovery for Pediatric Diseases)

Mini-Reviews in Medicinal Chemistry (2016)

Paul C. Trippier

Thematic map

10.2174/1389557516999160208143753

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CCDC 860456: Experimental Crystal Structure Determination

The Cambridge Structural Database (2012)

P. Angelov Y.K.S. Chau P.J. Fryer Mark G. Moloney A.L. Thompson

10.5517/ccxwcns

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DARK Classics in Chemical Neuroscience: Methamphetamine

ACS Chemical Neuroscience (2018)

Thomas J. Abbruscato Paul C. Trippier

Methamphetamine has the second highest prevalence of drug abuse after cannabis, with estimates of 35 million users worldwide. The (S)-(+)-enantiomer is the illicit drug, active neurostimulant, and eutomer, while the (R)-(−)-enantiomer is contained in over the counter decongestants. While designated a schedule II drug in 1970, (S)-(+)-methamphetamine is available by prescription for the treatment of attention-deficit disorder and obesity. The illicit use of (S)-(+)-methamphetamine results in the sudden "rush" of stimulation to the motivation, movement, pleasure, and reward centers in the brain, caused by rapid release of dopamine. In this review, we will provide an overview of the synthesis, pharmacology, adverse effects, and drug metabolism of this widely abused psychostimulant that distinguish it as a DARK classic in Chemical Neuroscience.

Methamphetamine

Clinical neuroscience

10.1021/acschemneuro.8b00123

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Citations (40)