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Dialectic Therapeutics’ mission is to create innovative new technologies to cure cancer. Our goal is to relieve the suffering of patients with cancer, to give them hope and prolong their productive lives through targeted therapies with limited toxicities and complications.


Dialectic Therapeutics (DT) is a pre-clinical biotechnology company dedicated to the development of unique, impactful anti-cancer drugs that effectively treat patients with few to no other options. DT was founded by three respected cancer scientists and two successful biotech investors and operators. DT is located in Dallas, Texas and has research partners and facilities at UT Health at San Antonio and the University of Florida Health Cancer Center.

DT’S LEAD CANDIDATE, DT2216, is a novel Antiapoptotic Protein Targeted Degradation  (APTaD™) compound that selectively induces cancer cells to degrade B-cell lymphoma extra large, or BCL-XL, stimulating the cells to commit suicide, or become more susceptible to chemotherapy.  DT2216 is currently in the IND-enabling phase as a single agent and combination therapy in liquid and solid cancer tumors and expects to enter the clinic in 2021.


Pre-clinical studies show that DT2216 is highly effective in various liquid and solid tumors as a single agent and in combination with chemotherapy.  Further, these studies show cancer cells are less likely to develop resistance to DT2216 than to other chemotherapy drugs. DT2216 accomplishes this with very little toxicity, particularly to platelets.


As with BCL-XL, there are many other significant proteins associated with cancer that cannot be targeted with current therapies.  APTaD™ is a novel approach that can be applied to the broader BCL family and other protein targets.  DT’s efforts are focused on developing drug candidates to address this high unmet need.  If successful, we will be able to provide cancer patients who have little hope with increased disease-free survival.


The DT team is focused on creating innovative new technologies to address late-stage difficult cancer diagnoses. We are comprised of protein degradation experts and leadership with a strong track record of clinical development and commercial success.




Dialectic Therapeutics Receives $3 Million Seed Award for Product Development Research from the Cancer Prevention & Research Institute of Texas
DALLAS, Feb. 26, 2020 /PRNewswire/ — Dialectic Therapeutics, Inc., a Texas-based biotechnology company focused on creating innovative new technologies to end cancer, today announced it has received a $3 million Seed Award for Product Development Research from the Cancer Prevention & Research Institute of Texas (CPRIT).



European Journal of Medicinal Chemistry
Discovery of IAP-recruiting BCL- XL PROTACs as potent degraders across multiple cancer cell lines
Xuan Zhang et al.
Targeting BCL-XL via PROTACs is a promising strategy in reducing BCL-XL inhibition associated platelet toxicity. Recently, we reported potent BCL-XL PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs. To overcome these mechanisms of resistance, PROTACs based on recruiting alternative E3 ligases could be generated. Thus, we designed and synthesized a series of PROTACs that recruit IAP E3 ligases for BCL-XL degradation. Among those PROTACs, compound 8a efficiently degrades BCL-XL in malignant T-cell lymphoma cell line MyLa 1929 while CRBN-based PROTACs that have high potency in other cancer cell lines show compromised potency, likely due to the low CRBN expression. Moreover, compared with the parent compound ABT-263, PROTAC 8a shows comparable cell killing effects in MyLa 1929 cells whereas the on-target platelet toxicity is significantly reduced. Our findings expand the anti-tumor spectra of BCL-XL degraders and further highlight the importance of selecting suitable E3 members to achieve effective cellular activity.


PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics
Sajid Khan et al.
Using PROteolysis TArgeting Chimeras (PROTACs) to degrade proteins that are important for tumorigenesis has emerged as a potential therapeutic strategy for cancer. PROTACs are heterobifunctional molecules consisting of one ligand for binding to a protein of interest (POI) and another to an E3 ubiquitin (E3) ligase, connected via a linker. PROTACs recruit the E3 ligase to the POI and cause proximity-induced ubiquitination and degradation of the POI by the ubiquitin-proteasome system (UPS). PROTACs have been developed to degrade a variety of cancer targets with unprecedented efficacy against a multitude of tumor types. To date, most of the PROTACs developed have utilized ligands to recruit E3 ligases that are ubiquitously expressed in both tumor and normal tissues. These PROTACs can cause on-target toxicities if the POIs are not tumor-specific. Therefore, identifying and recruiting the E3 ligases that are enriched in tumors with minimal expression in normal tissues holds the potential to develop tumor-specific/selective PROTACs. In this review, we will discuss the potential of PROTACs to become anticancer therapeutics, chemical and bioinformatics approaches for PROTAC design, and safety concerns with a special focus on the development of tumor-specific/selective PROTACs. In addition, the identification of tumor types in terms of solid versus hematological malignancies that can be best targeted with PROTAC approach will be briefly discussed.


Future Medicinal Chemistry
Assays and technologies for developing proteolysis targeting chimera degraders
Xingui Liu et al.
Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small molecules that can recruit an E3 ligase and a protein of interest (POI) into proximity, leading to induced ubiquitination and degradation of the POI by the proteasome system. To date, the design and optimization of PROTACs remain empirical due to the complicated mechanism of induced protein degradation. Nevertheless, it is increasingly appreciated that profiling step-by-step along the ubiquitin-proteasome degradation pathway using biochemical and biophysical assays are essential in understanding the structure–activity relationship and facilitating the rational design of PROTACs. This review aims to summarize these assays and to discuss the potential of expanding the toolbox with other new techniques.


Nature Communications
Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
Yonghan He et al.
Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.


European Journal of Medicinal Chemistry
Discovery of PROTAC BCL- XL degraders as potent anticancer agents with low on-target platelet toxicity
Xuan Zhang et al.
Anti-apoptotic protein BCL-XL plays a key role in tumorigenesis and cancer chemotherapy resistance, rendering it an attractive target for cancer treatment. However, BCL-XL inhibitors such as ABT-263 cannot be safely used in the clinic because platelets solely depend on BCL-XL to maintain their viability. To reduce the on-target platelet toxicity associated with the inhibition of BCL-XL, we designed and synthesized PROTAC BCL-XL degraders that recruit CRBN or VHL E3 ligase because both of these enzymes are poorly expressed in human platelets compared to various cancer cell lines. We confirmed that platelet-toxic BCL-XL/2 dual inhibitor ABT-263 can be converted into platelet-sparing CRBN/VHL-based BCL-XL specific degraders. A number of BCL-XL degraders are more potent in killing cancer cells than their parent compound ABT-263. Specifically, XZ739, a CRBN-dependent BCL-XL degrader, is 20-fold more potent than ABT-263 against MOLT-4 T-ALL cells and has >100-fold selectivity for MOLT-4 cells over human platelets. Our findings further demonstrated the utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases.


Future Medicinal Chemistry
Targeting anti-apoptotic BCL-2 family proteins for cancer treatment
Xuan Zhang et al.
Apoptosis, also known as programmed cell death, contributes to cellular homeostasis, normal development and clearance of abnormal cells. Dysregulation of apoptotic pathways plays an important role in tumorigenesis and is considered to be one of the hallmarks of cancer. Moreover, resistance to apoptosis is associated with desensitization to conventional cytotoxic and targeted therapies. Therefore, the induction of cell death by targeting apoptotic pathways is an attractive therapeutic strategy. BCL-2 family proteins are the key regulators of the mitochondria-mediated apoptotic pathway and can be divided into three subsets; pro-apoptotic BH3-only proteins (apoptosis initiators, such as BIM, BID and PUMA), pro-apoptotic proteins BAK and BAX (apoptosis effectors) and anti-apoptotic proteins (apoptosis gatekeepers, such as BCL-2, BCL-XL, MCL-1 and BCL-w) [3]. Among those, several anti-apoptotic members including BCL-2, BCL-XL, and MCL-1 are well-validated anticancer targets. Displacement of pro-apoptotic proteins from the binding groove of anti-apoptotic members results in homo-oligomerization of BAK and BAX, permeabilization of mitochondrial outer membrane, release of cytochrome c and activation of caspases to trigger apoptosis


Nature Medicine
A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity
Khan, S. et al.
B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.


Chemical Communications
Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL- XL
Xuan Zhang et al.
BCL-XL, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-XL as an anti-cancer target has been hampered by the on-target platelet toxicity because platelets depend on BCL-XL to maintain their viability. Here we report the development of a PROTAC BCL-XL degrader, XZ424, which has increased selectivity for BCL-XL-dependent MOLT-4 cells over human platelets compared with conventional BCL-XL inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.

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