| Drug Name | PPM-100 |
| Description | PPM-100 is a molecular glue degrader specifically engineered to degrade DNA-binding protein Ikaros (IKZF1) and zinc finger protein Aiolos (IKZF3). It is being developed in preclinical studies for the treatment of blood cancers and solid tumors. |
| Target | IKZF1/3 |
| Drug Modality | Molecular glue degrader |
| Indication | Blood cancers and solid tumors |
| Product Category | Signal transduction modulators |
| Mechanism of Action | Degradation of IKZF1 and IKZF3 |
| Status | Preclinical |
| Patent | Granted |
Protheragen Inc. is actively seeking partnership for PPM-100. Potential collaboration can be strategic alliance, licensing, or marketing agreement.
We look forward to hearing from you.
| Introduction | DNA-binding protein Ikaros, also known as IKAROS family zinc finger 1 (IKZF1), is a protein encoded by the IKZF1 gene in humans. IKZF1 is a member of the lymphoid-restricted zinc finger transcription factor family that regulates lymphocyte differentiation and proliferation. It regulates transcription through chromatin remodeling and epigenetic modification, and affects signaling pathways critical for lymphocyte differentiation, such as PI3K/AKT, IL-7 signaling, and integrin-dependent cell survival. |
| Approved Name | IKAROS family zinc finger 1 |
| Official Symbol | IKZF1 |
| Gene Type | Gene with protein product |
| Synonyms | hIk-1; LyF-1; Hs.54452; IKAROS; PPP1R92 |
| Ensembl | ENST00000331340.8 |
| Gene ID | 10320 |
| mRNA Refseq | NM_006060 |
| Protein Refseq | NP_006051.1 |
| OMIM | 603023 |
| UniProt ID | Q13422 |
| Chromosome Location | 7p12.2 |
| Introduction | IKAROS family zinc finger 3 (IKZF3), also known as Aiolos, is also a member of the lymphoid-restricted zinc finger transcription factor family that is involved in the regulation of lymphocyte development. IKZF3 is important in the regulation of B lymphocyte proliferation and differentiation. IKZF3 participates in chromatin remodeling. Regulation of gene expression in B lymphocytes by IKZF3 is complex as it appears to require the sequential formation of IKZF1 homodimers, IKZF1/3 heterodimers, and IKZF3 homodimers. |
| Approved Name | IKAROS family zinc finger 3 |
| Official Symbol | IKZF3 |
| Gene Type | Gene with protein product |
| Synonyms | Aiolos |
| Ensembl | ENST00000346872.8 |
| Gene ID | 22806 |
| mRNA Refseq | NM_012481 |
| Protein Refseq | NP_036613.2 |
| OMIM | 606221 |
| UniProt ID | Q9UKT9 |
| Chromosome Location | 17q12-q21.1 |
PPM-100 is a unique molecular glue that is expected to possess superior pharmacological properties comparing to PROTACs with smaller molecule weight, better oral bioavailability, higher membrane permeability and better cellular uptake. PPM-100 is one of PPM molecular glue degraders with pleiotropic activities that are proved to selectively kill several types of cancer cells, stimulate T and NK cell activation, and downregulate synthesis of inflammatory mediators. These PPM molecular glue degraders have great potentials for immunotherapy of cancers, chronic inflammation, and other conditions as a monotherapy or in combinations with other agents.
Advantages of PPM Molecular Glue Degraders
| PROTACs | Molecular glues | PPM Molecular glues | |
| Features | bivalent | monovalent | monovalent |
| Links | yes | no | no |
| MW (Dalton) | 700-1000 | <500 | <500 |
| Lipinski’s rule of five | defy | within | within |
| Target protein | predictable | to be determined | clear enzymes |
| Degradation of target protein | yes | yes | yes |
| Inhibition of target protein activity | unclear | unclear | yes |
| Binding pocket | required | not required | required |
| Binding affinity | strong affinity to E3 ligase and the target protein; two ligands are connected by a linker | weak affinity for either E3 ligase or target protein is needed; display an event driven catalytic MoA | weak affinity for either E3 ligase or target protein is needed; display an event driven catalytic MoA |
| Potential for solid tumors | yes/no | yes/no | yes |
| Immunomodulation | unclear | unclear | yes |
| Anti-inflammation | unclear | unclear | yes |
Molecular glues are a unique type of small molecular compounds that degrade, stabilize, or activate target proteins upon binding, thereby altering protein-protein interactions. Small-molecule molecular glues have great potential applications in the treatment of human diseases, including cancers. Molecular glue can target essentially any protein that plays a key role in the etiology of cancers, and among these protein targets there are many that were previously considered undruggable. Molecular glue recruits the target protein to an enzyme that for proteasomal degradation and they may be a viable therapeutic alternative for many cancer-related proteins that are not well targeted by conventional small molecules.
Cancers are divided into solid tumors and blood cancers and most of them are lethal. Solid tumors appear to be more biologically complex than blood cancers, with redundant pathways and drug-delivery challenges. Solid tumors are formed by the accumulation of abnormal tissues that do not contain any fluid or cysts and are classified as benign or malignant. The solid tumor market was valued at USD 209.61 billion in 2021 and is expected to reach USD 901.27 billion by 2029, registering a CAGR of 20.0% during the forecast period from 2022 to 2029. Unlike solid tumors that arise from organs or tissues, blood cancers (also known as hematologic tumors) originate from blood cells. It is predicted that there will be about 1.85 million new cases of hematological cancers worldwide in 2040, including 918,872 cases of lymphoma, 656,345 cases of leukemia, and 275,047 cases of myeloma. The blood cancer market was valued at USD 43.71 billion in 2021 and is expected to reach USD 89.68 billion by 2029, registering a CAGR of 9.40% during the forecast period 2022-2029.
KZF1 and IKZF3 are lymphocyte transcription factors that are key regulators of malignant plasma cell survival in multiple myeloma. In addition, they are of great importance in the occurrence, metastasis, and prognosis of other hematological malignancies and solid tumors. Since IKZF1 and IKZF3 lack druggable binding pockets, they are considered as undruggable target proteins. Acting as molecular glue, PPM-100 can promote ubiquitination and degradation of IKZF1 and IKZF3. PPM-100 is expected to possess superior pharmacological properties comparing to PROTACs with smaller molecule weight, better oral bioavailability, higher membrane permeability, and better cellular uptake.
PPM-100 is under preclinical development. In vitro, PPM-100 showed cytotoxicity on a variety of cancer cells including human myeloma cells, prostate cancer cells, breast cancer cells, renal cancer cells, and colorectal cancer cells, as well as caused the degradation of c-MYC in cancer cells, the decrease of proinflammatory cytokines, the increase of T cells activation and so on.
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Disruption of Cell Cycle Progression in OCI-Ly3 Human Lymphoma CellsOCI-Ly3 non-Hodgkin’s lymphoma cells were treated with PPM-100 for 24 hours. The results showed the cell cycle progression was disrupted. |
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Degradation of c-MYC in SKBR3 Human Breast Cancer CellsSKBR3 breast cancer cells were treated with PPM-100 overnight. As shown, PPM-100 caused the degradation of c-MYC (a master regulator of cancer cell metabolism) in the SKBR3 cells. |
Protheragen's business is growing rapidly after founded in New York. Our business has evolved from the initial intermediary service to encompass segments in equity investment and program incubation.
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