Translational Experimental Therapeutics

Formerly Drug Discovery & Nanomedicine, the Translational Experimental Therapeutics (TET) research program at SJCI fosters the development of innovative chemical solutions to the limitations of drugs currently utilized in clinic. We focus on solving problems in a multidisciplinary chemical and biologically informed manner, in contrast to the traditional pharma drug development model. Our vision is to build a premiere research program recognized for its contributions to translational research and the discovery of novel experimental therapeutics for treatment of human disease and improvement of patient survival.

Translational Experimental Therapeutics

Goals and Objectives

Dr Yenugonda - Drug Discover - Saint John's Cancer Institute
Dr. Yenugonda advances ongoing translational drug discovery projects at the Saint John’s Cancer Institute

The overall goal of the TETR Program is to discover and validate novel therapeutic targets, and develop safe, effective, and patentable experimental drugs and treatment strategies for cancer. A primary objective of the TETR Program is identification of clinically relevant new cancer therapies paired with laboratory research to facilitate translational research. Our research has a strong clinical and translational orientation, aligned along four main fast and cost-effective research themes depending on the demands of the project.

  • Drug Discovery:  Multidisciplinary chemical (New drug/Repurposed) approaches towards discovery of novel patentable experimental therapeutics in Oncology and CNS disease targets and biomarkers.
  • Drug Delivery:  Develop novel lipid-based nanoparticle and small molecule drug conjugated prodrug delivery platforms to enhance cancer therapy.
  • Combination Therapy:  Combine immunotherapy and standard-of-care therapy (chemotherapy and radiation), with our lead experimental drugs to increase overall treatment efficiency and improve patient outcomes.
  • Clinical Research:  Fostering translation of discoveries between the laboratory and clinic through collaborations and scientific synergy among SJCI members.

TETR Program Services

The Translational Experimental Therapeutic (TET) research program offers a variety of drug discovery /development and delivery services for SJCI internal and external principal investigators, depending on their project needs. Our program allies with top level academic institutions and custom research organization companies to bring our ideas to fruition. Listed below are some of the major activities of TETR program.

soluble-efficacious-safe-cell permeable-selective
TETR promotes drug discovery and formulation that is safe and effective – Saint John’s Cancer Institute.
  1. In Silico Drug Discovery:  Our program supports a variety of computational-aided drug design (CADD) methods to identify new chemical entities for druggable and undruggable disease targets of your interest.
  2. Medicinal Chemistry And Structure-Activity Relationship (Sar):  Our program supports the building of a diversified and focused chemical scaffold library for your hits, to perform SAR studies and identify patentable lead analogs.
  3. Drug Target Engagement Studies:  Our program supports the design of a variety of cell free and cell-based target engagement studies to validate experimental drugs for biomarker mediated mechanistic studies. We further apply -omics methods to understand signaling pathways and identify the most vulnerable patient population for lead experimental drugs.
  4. Resistance Mechanism and Combination Studies:  Our program investigates the resistance mechanisms of lead experimental drugs and addresses this by developing drug combinations.
  5. Drug Metabolism, Pharmacokinetics and Pharmacodynamics: Our program can coordinate preclinical studies to establish experimental drug pharmacology and toxicity profiles, to allow for dose adjustment and optimization of the route of administration.
  6. Drug Formulations:  Our program supports developing lipid-based nanoparticle formulations and small molecule drug conjugate pro-drug formulations to improve the therapeutic index of experimental drugs as well as clinically active drugs.
  7. Grant Support:  In addition to the above services, our program will help you build specific aims for your project and identify suitable grant agencies for the best chance at success in securing funding.

Our multidisciplinary services are proven to translate your biology insights to meaningful patentable therapeutics.

Current Research Focus

SJCI’s TETR is an interdisciplinary program, uniting diversified scientists and clinicians specializing in a wide range of fields, including experimental therapeutics (drug discovery), nanoparticle, cancer biology, biochemistry, immunology, molecular pharmacology, medical oncology, and surgery. Over the past three years, our program has already taken on several translational experimental therapeutic projects for cancer and neurodegenerative diseases. Several research projects have matured to the stage of preclinical IND. These discoveries hold promise for many cancers, both common and rare, and represent the full spectrum of therapeutic modalities including experimental therapeutics, drug delivery, and combination therapy. Our unique skills and collaborations have made SJCI’s TET research program successful in the development of novel therapeutics to address clinically challenging problems.

Our program applies the following methods to maximize the success of the translational projects in a quick and efficient manner including:

Drug Discovery Collaboration - Saint John's Cancer Institute
Saint John’s Cancer Institute employs a
multidisciplinary approach, empowering a collaborative team environment.
  • Informed and levelheaded decision making under tight timelines
  • Minimizing costs and time and maximizing success by starting with innovative project design
  • Multidisciplinary background allows for effective communication between chemistry and biology teams
  • Emphasizing a collaborative team environment internally and externally to reach goals more effectively
  • Fostering positive energy and respect among team members

To ensure that the most promising ideas are funded, we submit grant applications which are subjected to a competitive peer-review process modeled on that of the National Institutes of Health, Department of Defense, and other private foundations. The TET research program welcomes research projects for therapeutic development in any type of cancer and particularly favors collaborative research projects in which multiple investigators with different expertise focus on a specific type of cancer or treatment modality.

Active In-house Translational Research Projects:

  • Disease Areas: Triple Negative Breast Cancer, Glioblastoma, SARS CoV-2 and Alzheimer’s Disease

Active Collaborative Translational Research Projects:

  • Disease Areas: Diffuse Intrinsic Pontine Glioma, Medulloblastoma, ER+ Breast Cancer Resistance, metastatic castration resistance Prostate Cancer, Addiction

Triple Negative Breast Cancer:

Triple negative breast cancer - sub types and survival
Triple Negative Breast Cancer – sub types and survival

Clinical Significance:  Breast cancer (BC), a leading cause of death in women worldwide, comprises three major pathological subtypes: ER+, HER2+, and triple-negative Breast Cancer (TNBC). TNBC represents 15–20% of breast cancer cases but accounts for 25% of deaths. TNBCs are highly heterogeneous and aggressive diseases. Gene analysis indicates that 70–80% of TNBC are of the highly aggressive subtype, Basal like Breast Cancer (BLBC, TNBC), that will initially respond to chemotherapy but eventually develops resistance, metastasis, and post-surgical re-occurrence. This poor outcome derives from the heterogeneous nature of the disease, coupled with a lack of biomarkers that are necessary for therapy. There is an urgent need to improve our understanding of the molecular basis for BLBC, to discover effective therapeutic targets to improve the outcome in patients.

Our Approach:  In recent years, genetic analyses have helped delineate the molecular landscape of TNBC. Prior studies have revealed various mutations in TNBC with many arising in tumor suppressors, genes that typically regulate cell growth but can result in cancer if lost through mutation. Despite these findings, there remain few treatments to target tumor suppressor loss in TNBC. Specifically, the retinoblastoma (RB) tumor suppressor is frequently lost in TNBC, occurring in an estimated 30% of cases. Typically, the RB tumor suppressor plays a key role in cell cycle regulation. However, if mutated, the RB tumor suppressor cannot inhibit cell cycle progression, contributing to tumorigenesis. While there have been recent developments in treatments for hormone-receptor-positive and some subtypes of TNBC with CDK 4/6 inhibitors, these therapies rely on an intact RB for success. Due to the high frequency of RB loss and current absence of effective therapies, efforts to develop selective therapies for RB loss in TNBC are needed. We have developed novel experimental drugs that effectively kill TNBC cells with RB loss.


Glioblastoma Multiforme:

Glioblastoma Multiforme - Saint Johns Cancer Institute

Clinical Significance:  Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults. Despite advances in understanding the molecular mechanisms underlying GBM tumorigenesis, most current targeted therapies have proven ineffective and temozolomide (TMZ) has remained the cornerstone of GBM treatment. Radiation and TMZ followed by adjuvant TMZ show significant improvement in GBM patient survival, but all tumors ultimately recur, leaving median survival at only 12-15 months.

Unfortunately, TMZ treatment is primarily effective only in late stage GBM tumors, when the tight junctions around the BBB have degraded and become “leaky”; in early stage GBM, the tight junctions around the intact blood brain barrier (BBB) prevent adequate TMZ dosing at the tumor site. Increasing the dose to increase efficacy is not an option, due to the severe dose limiting myelosuppressive toxicity, unrelated to the CNS. Furthermore, over 50% of GBM patients treated with TMZ do not respond to the therapy due to intrinsic, MGMT driven resistance, and those that do respond eventually develop TMZ-resistant recurrent tumors. There is clearly a need for alternative chemotherapeutic options in the clinic. The development of a new class of TMZ-like analogs, with improved brain-to-plasma ratios (which might minimize the myelosuppressive toxicity), encapsulated into tumor targeted nano-carriers that maximize their therapeutic efficiency (and can bypass the intact BBB) can address these persistent clinical limitations.

Our Approach: Our lab has developed and synthesized a series of novel TMZ analogs, designed to have improved blood to plasma ratios. These analogs were structurally characterized, evaluated, and then ranked according to their efficacy and brain permeability. During this process we identified an initial lead compound named VMY-TP9. Our lead TP9 has a greater brain-to-plasma ratio (>3-fold) than TMZ, when administered both intravenously and orally. TP9 showed promising inhibitory activity in tumor cells that are highly TMZ-resistant (T98G) and produced DNA damage effects for a prolonged period. In an initial GBM animal model study, our lead TP9 was well tolerated (no change on body weight) and showed a slightly better neutrophil count (bone marrow toxicity) in mice at the tested dose compared to TMZ, while showing similar tumor growth inhibition.

SARS CoV-2:

Computational model of Natural Products binding to the SARS-CoV- 2 spike protein
Computational model of Natural Products binding to the SARS-CoV- 2 spike protein (courtesy JB Laboratory)

The COVID-19 pandemic is an ongoing medical health emergency worldwide, and significant efforts are underway to develop detection tools, treatment options, and prevention modalities to manage it. Similar to many other viruses, the SARS-CoV-2 virus binds to and enters into a host cell to hijack its cellular machinery to proliferate and spread infections. Studies have shown that SARS-CoV-2 uses the spike protein (SP) protruding from its surface, to target and bind to the ACE2 protein located on the membrane of human lung tissue. Before the virus can fully enter and infect the host cell, the spike protein is also cleaved by other proteins on the cell surface, furin and TMPRSS2.

Blocking viral entry into host cells is one of the most effective ways to prevent infection and serious illness. Anti-SARS-CoV-2 vaccines and neutralizing antibodies have been developed to block the infection by the virus, but they may not be sensitive to new viral strains appearing worldwide, and (for neutralizing antibodies) they unfortunately show only limited potency. Furthermore, antibody mediated therapies are financially burdensome to both patients and the healthcare system. Considering these issues, the preferred approach of pharmaceutical development is an orally bioavailable small molecule targeting the spike protein. A small molecule would have many advantages over vaccines and ‘biologics’: small molecule pharmaceuticals are effective, affordable and easy to administer. Using advanced computational methods (molecular dynamics and structure- guided drug-binding analysis), we have already identified initial hits that bind to the SARS- CoV-2 spike glycoprotein.

Our present work is mainly focused on prioritizing the best natural compounds from these hits, with ideal chemical profiles for preclinical and clinical efficacy and potency. To achieve these goals, we will measure the Drug/ACE2 interaction inhibition in invitro assays. Mapping the mechanism of action of these compounds will lead to the development of new therapeutics for SARS-CoV-2. Our approach is a highly cost-effective method of rapidly identifying natural small molecule inhibitors that can efficiently bind to the SARS-CoV-2 spike protein and prevent COVID-19 infection.

Alzheimer’s Disease:

TET research program developing new experimental p25 inhibitors
The TET program is developing new experimental p25 inhibitors to block the tau hyperphosphorylation and minimize tangles formation in AD.

Clinical Significance:  Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which affects about 5.5 million people in the United States and 40 million worldwide. There is an urgent need to develop new therapeutic approaches as the current FDA approved medications have no effects on the progression of the disease. it is estimated that by 2050, 12 million people in the United States will have AD (Alzheimer’s, 2015). Accumulation of amyloid-b (Ab) protein and hyper-phosphorylated tau protein are critical events in the pathogenesis of AD. Pathological tau aggregates eventually form toxic neurofibrillary tangles (NFTs), characteristic of AD and other neurodegenerative tauopathies.

Our Approach:  Many drugs have been developed to target Ab and NFTs directly, and all have failed in the past few decades. We are focused on developing new drugs to target high impact early targets that have roles in developing Alzheimer’s: CDK5/p25. The abnormally active CDK5 protein plays a major role in the over-activation of tau and is the most damaging step in NFT formation. Cyclin dependent kinase-5 (CDK5) inhibitors an attractive and innovative approach towards preventing tau hyperphosphorylation.

We performed a high-end computer aided drug design virtual screen to identify CDK5-p25 inhibitors. We identified pockets on either CDK5, p25, or at the interface of the CDK5-p25 complex and employed a virtual screening (structure and ligand based) protocol to identify suitable binders in the pockets. This is the first time where we introduced six virtual screening protocols into the CDK5/p25 complex to identify several highly selective and potent inhibitors that inhibit p25 activity.


In addition, the TETR program is actively collaborating with other academic institutes to develop novel experimental therapeutics for various CANCER and CNS disease targets.

TETR Collaborators - Saint John's Cancer Institute

Meet Our Team

Dr. Yenugonda, M.Phil, PhD, FNAI., Associate Professor, Director of Translational Experimental Therapeutics Research Program, serves as Principal Investigator along side internal and external collaborative multiple PI’s. The TETR program focuses on patient-centric innovations in therapeutics and producing clinically relevant contributions to drug research. As PI, Dr. Yenugonda focuses on three fast and cost-effective research approaches: precision drug discovery nano liposomal drugs/RNAi, and combination therapy. The precision strategy is multidisciplinary, combining chemical and genomic profiling of disease models with computational modeling to identify (1) drugs and their mechanisms of action (2) the key pathways associated with each drug response, and (3) combinatorial interventions based on drug-pathway associations. Over the past four years, our program has already taken on several translational drug discovery projects for cancer, neurodegenerative disease, and neurological disorders from design to clinical drug candidate development. We have secured funding for several translational drug discovery projects, ranging from target identification through proof-of-concept (POC) clinical trials.

Partnerships and Collaborations

The TETR research program is constantly seeking new opportunities to collaborate, welcoming informal discussions within and outside the institute. When discussing a new collaborative project, we consider several factors including the clinical relevance of the disease targets, therapeutic innovation, project significance, and compatibility. Our program brings together cancer researchers from a variety of disciplines that focus on:

  • Identifying potential new therapeutics for novel CANCER and CNS targets
  • Developing experimental drugs that maximize the therapeutic efficacy
  • Designing and evaluating drug target ID engagement and mechanisms of action
  • Improving the therapeutic index and minimizing side effects of anti-cancer approved and experimental drugs
  • Generating “Hit to Lead” like drugs for patent protection
  • Designing preclinical-IND enabling studies to evaluate the safety and toxicity of experimental drugs for phase studies
  • Identifying the right combination of anti-cancer drug treatment options to maximize efficacy and reduce the side effects
Saint John's Cancer Institute - Partnerships

Publications

Dr. Yenugonda has published and co-authored 32 peer-reviewed publications. See full list at NIH.gov.

   NANO LIPOSOMAL AND PRODRUG THERAPEUTICS

  1. Lipid-Polymer hybrid nanoparticles as a next generation drug delivery platform : state of the art, emerging technologies and perspectives. Int J Nanomedicine 2019, 19, 1937-1952.PMID: 30936695

    Mukherjee, A.; Waters, A. K.; Kalyan, P.; Achrol, A.S.; Kesari, S.; Yenugonda, V. M.

  2. Antibody drug conjugates: Progress, pitfalls, and promises. Hum Antibodies 2019, 27, 53-62.PMID: 30223393

    Mukherjee, A.; Waters, A. K.; Babic, I.; Nurmemmedov, E.; Glassy, M. C.; Kesari, S.; Yenugonda, V. M.

  3. Cationic amphiphile with shikimic acid headgroup shows more systemic promise than its mannosyl analogue as DNA vaccine carrier in dendritic cell based genetic immunization. Med. Chem. 2010, 53, 1387-1391. PMID: 20050668.

    Srinivas, R.; Karmali, P. P.; Pramanik, D.; Garu, A.; Yenugonda, V. M.; Majeti, B. K.; Ramakrishna, S.; Srinivas, G.; Chaudhuri, A.

  4. Cationic glycolipids with cyclic and open galactose head groups for the selective targeting of genes to mouse liver. 2009, 30, 2369-2384. PMID: 19157538.

    Mukthavaram, R.; Marepally, S.; Yenugonda, V. M.; Vegi, G. N.; Sistla, R.; Chaudhuri, A.

ONCOTHERAPEUTICS

  1. Novel temozolomide analogs to improve anti-tumor efficacy and overcome resistant in glioblastoma multiforme. Neuro-Oncology, Volume 22, Issue Supplement_2, November 2020, Pages ii66–ii67

    Waters, A.; Tomimatsu,N.;  Babic,I.;  Nurmemmedov, E.; Allnutt, A.; Quan, Y.;   Natsuko Nomura, N.;  Burma, S.; Kesari, S.; Yenugonda, V.M.

  2. Small molecule targeting regulated cell death pathways in treating triple negative breast cancer. Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019. Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl): Abstract nr P5-05-12.

    Waters, A.; Yadavalli, S.;  Marzese, D.; Orry, A.; Senugupta, S.;  Quan,Y.; Nomura, N.;  Allnutt, A.; Kesari, S.;  Yenugonda, V.M.

  3. A Novel Small Molecule Inhibitor of Mitochondrial. J Transl Med 2017, 15, 210. PMID. 29047383

    Yenugonda, V.M.; Nomura, N.; Kouznetsova,V.; Tsigelny, I.; Fogal, V.; Yang, J.; Nurmemmedov, E.; Kesari, S.; and Babic, I.

  4. The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells. Aging (Albany NY) 2015, 7, 854-68, PMID: 26540407.

    Waye, S.; Naeem, A.; Choudhry, M.U.; Parasido, E.; Tricoli, L.; Sivakumar, A.; Mikhaiel, J.P.; Yenugonda, V.M.; Rodriguez, O.C.; Karam, S.D.; Rood, B.R.; Avantaggiati, M.L and Albanese.C.

NEUROTHERAPEUTICS

  1. Roles of Cdk5: Potential Directions for Therapeutic Targeting in Neurodegenerative Disease. ACS Chem Neurosci 2020, 11 (9), 1218-1230. PMID: 32286796

    Allnutt, A. B.; Waters, A. K.;  Kesari, S.; Yenugonda, V. M.

  2. Design, Synthesis and Discovery of Picomolar Selective alpha4beta2 Nicotinic Acetylcholine Receptor Ligands. Med. Chem. 2013 56(21): 8404-21. PMID: 24047231.

    Yenugonda, V.M.; Xiao,Y.; Levin,E.D.; Rezvani, A.H.; Tran,T.; Al-Muhtasib, N.; Sahibzada, N.; Xie, T.; Wells, C.; Slade, S.; Johnson, J. E.; Dakshanamurthy, S.; Kong, H. S.; Tomita,Y.; Liu,Y.; Paige,M.; Kellar,K.J.; Brown,M.L.

  3. Chemistry and pharmacological studies of 3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel selective α4β2 nicotinic acetylcholine receptor ligands that reduce alcohol intake in rats. Med. Chem. 2013, 56, 3000-11. PMID: 23540678.

    Liu, Y.; Richardson, J.; Tran, T.; Al-Muhtasib, N.; Xie, T.; Yenugonda, V. M.; Sexton, H. G.; Rezvani, A.H.; Levin, E. D.; Sahibzada, N.; Kellar, K. J.; Brown, M. L.; Xiao, Y.; Paige, M.

Our Supporters

We would like to thank the below funding supporting sources in support of our research. Without this support, we would not be able to advance in developing novel lead experimental drugs for treating Cancer and Neurodegenerative disease.

Experimental Therapeutics Supporters 2021

Donations:

If you would like to make donations, please make checks payable to:

Saint John’s Cancer Institute TET Research Program
2200 Santa Monica Blvd
Santa Monica, CA 90404

News and Events:

UAH’s Baudry Lab part of half-million-dollar efforts to target COVID with drug therapies

Dr. Venkata Maidhar Yenugonda, M.Phil, Ph.D., Director, Drug Discovery and Nanomedicine Laboratory, lends his scientific expertise as part of the SARS CoV-2 research grant recently awarded by St. John’s Cancer Institute.
See full story at uah.edu/news
JUL 29, 2021 | Jim Steele

2021 Conferences and Invited Speakers:

Invited Speaker
3rdInternational Conference on  PHARMA R&D-2021 (Feb 22, 2021)

Keynote Guest Speaker
8th International Conference on Brain Disorders and Therapeutics
London, UK
September 15-16, 2021

Poster Presentation
47th Annual Meeting of Korean Cancer Association and 7 th International Cancer Conference

Career Opportunities:

The TET research program is always looking for talented and enthusiastic individuals at all levels who are interested in becoming a part of our team developing new therapeutics for unmet medical needs.

We currently have openings for the following opportunities:

  • Student Interns and Research Associate positions that are open currently.

To apply, please contact:

Venkata Mahidhar Yenugonda , M.S., Ph.D.
Program Director
yenugondav@providence.org
vmy@jwci.org