作者: Long, Marissa ; Parchinsky, Vladislav ; Bryant, Kinsey ; Hertlein, Erin K. ; Elgamal, Sara ; Kysil, Volodymyr ; Gukasyan, Hovhannes ; Abagyan, Ruben ; Bulanova, Elena ; Dokukina, Kate ; Savchuk, Nikolay ; Karapetian, Ruben ; Lerma, James R. ; Orry, Andrew ; Ryakhovskiy, Alexey ; Burd, Amy ; Fobare, Sydney ; Sharpe, Chia ; Furby, Casie ; Cheney, Carolyn ; Lam, Polo Chun-Hung ; Byrd, John C. ; Johnstone, Megan E. ; Ivachtchenko, Alexandre ; Mitkin, Oleg ; Pushechnikov, Alexei ; Dukes, Iain

BCL2 is a key pro-survival protein that is overexpressed in many cancers. The first generation BCL2 inhibitor venetoclax has proved highly effective in multiple hematological malignancies including CLL and AML. However, the pharmacokinetic half-life of venetoclax is 26 hours which prevents optimization of the therapeutic window. Additionally, venetoclax metabolism is influenced by Cyp3A/4 inhibitors making their use in diseases where anti-fungal prophylaxis is required challenging. Venetoclax treatment can also result in significant immunosuppression including dose-limiting neutropenia and thrombocytopenia, and the loss of multiple lymphocyte populations, due in part to its effect on BCL-xL. Herein we present the pre-clinical evaluation of a novel highly selective BCL2 inhibitor, ZE50-0134, with equivalent anti-tumor efficacy, improved safety profile, and limited impact on non-malignant immune populations.ZE50-0134 binds the P2 pocket of BCL2, thereby increasing selectivity toward BCL-2, ZE50-0134 showed a 4600-fold greater selectivity for BCL2 over BCL-xL compared to venetoclax with only an 84-fold greater selectivity. In vivo murine and canine pharmacokinetics showed that ZE50-0134 has a substantially shorter half-life than venetoclax suggesting feasibility for periodic pulse dosing to limit the on-target adverse effects of BCL2 inhibition. The ADME properties of ZE50-0134 were exceptional. An in vivo murine study examining the pharmacology of ZE50-0134 or venetoclax given with ketoconazole, a strong CYP3A inhibitor, was performed demonstrating a 0.84-fold decrease in AUC with ZE50-0134 vs. a 1.52-fold increase in AUC with venetoclax suggesting less Cyp3A influence on ZE50-0134. Toxicology in rats and dogs suggest a 19-fold margin between therapeutically effective dose and toxicity with ZE50-0134.Given this data, we sought to validate that ZE50-0134 has less impact on normal immune populations. Wild-type C57BL6/J mice were treated daily with 100 mg/kg ZE50-0134, 100 mg/kg venetoclax or vehicle. A comprehensive 36-color spectral flow cytometry immune profiling panel was used to evaluate the effect of BCL2 inhibitors on multiple immune populations including B, T and NK cells as well as monocyte/macrophage and dendritic cell subsets in the peripheral blood. Venetoclax treated mice demonstrated a significant loss of multiple lymphocyte populations, including B, T, and NK cells, in the peripheral blood. Particularly, from Day 14 venetoclax treatment significantly reduced the percentage and absolute count of CD8 T cells (Figure 1). Some reduction in CD8 T cells was also observed with ZE50-0134 treatment, however it was significantly less than with venetoclax. No changes in the frequency of any normal myeloid population were observed.We next sought to examine the effectiveness of ZE50-0134 in B-cell and myeloid malignancies. Primary CLL cells were treated for 4 and 24 hours, corresponding to the expected half-life of ZE50-0134 and venetoclax, followed by washout. Cytotoxicity at 72 hours for both ZE50-0134 and venetoclax were equivalent for both short and prolonged treatment. We then assessed ZE50-0134 and venetoclax in vivo at 100 mg/kg in the RSV4;11 subcutaneous lymphoid model where we observed similar tumor growth regression. In AML, venetoclax is typically not effective as monotherapy and if often used in combination with azacytidine. To assess the relative efficacy of venetoclax and ZE50-0134 in combination with Azacitidine (5-Aza), we used the MOLM-13 cell line disseminated xenograft model. NCG mice were engrafted with MOLM-13 cells via the tail vein. From day 3, mice were treated with daily oral gavage of venetoclax or ZE50-0134 (100 mg/kg) alone or in combination with weekly intravenous 5-Aza (2.5 mg/kg). ZE50-0134 and venetoclax performed equally as single agents (median survival 23.5 days vs 22.5 days) and in combination with 5-Aza (median survival 35 days vs 35 days) (Figure 2).Together, this data suggests that ZE50-0134 is a highly effective BCL2 inhibitor with substantially less impact on the normal immune cells responsible for both anti-tumor and anti-infectious immunity. The pharmacology of this agent makes it an ideal therapeutic to optimize tumor BCL2 dependence and avoid untoward toxicity that occurs through continuous BCL2 targeting. This data supports the further clinical development of ZE50-0134 in both B cell malignancies and AML.

2023-11-02·Blood

Therapeutic Targeting of FLT3 Gate Keeper Mutation with E2082-0047 in Traditional and a Novel Immunocompetent Murine Adoptive Transfer Model of AML

作者: Furby, Casie ; Hertlein, Erin K. ; Bryant, Kinsey ; Dokukina, Kate ; Pan, Jianmin ; Savchuk, Nikolay ; Ryakhovskiy, Alexey ; Abagyan, Ruben ; Rai, Shesh N. ; Byrd, John C. ; Johnstone, Megan E. ; Li, Haishan ; Sesterhenn, Thomas M. ; Pauza, C. David ; Sharpe, Chia ; Dukes, Iain ; Lerma, James R. ; Ivachtchenko, Alexandre ; Starczynowski, Daniel T. ; Parchinsky, Vladislav ; Elgamal, Ola A. ; Lam, Polo Chun-Hung ; Fyock, Kaytlynn ; Gukasyan, Hovhannes ; Stearns, Blaise ; Long, Marissa ; Zapata, Juan Carlos ; Burd, Amy ; Fobare, Sydney ; Wronowski, Benjamin ; Orry, Andrew ; Mitkin, Oleg ; Bulanova, Elena ; Karapetian, Ruben ; Kysil, Volodymyr ; Pushechnikov, Alexei

Signaling mutations such as Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD) occur in approximately 30% of AML patients which provide AML cells with a constitutively active aberrant growth advantage, resulting in inferior overall survival. Multiple phase 3 studies with different FLT3 inhibitors validated FLT3-ITD as an important therapeutic target in AML. However, resistance to FLT3-ITD inhibitors occurs via mutations in the tyrosine kinase domain (FLT3-TKD), including the gatekeeper mutation F691L for which all approved FLT3 inhibitors are ineffective. Other mechanisms of secondary FLT3 inhibitor resistance include induction of IRAK4 activity and acquisition of RAS/PTPN11/MAPK activating mutations. New FLT3 inhibitors targeting both intrinsic (FLT3 acquired mutations) and extrinsic mechanisms of FLT3 resistance (e.g. IRAK4 induction) are urgently needed.We demonstrated previously the selectivity and potency of a novel FLT3 inhibitor, E2082-0047, against FLT3-ITD and TKD mutations in vitro using a Ba/F3 cell line harboring different TKD mutations. Guided by KinomeScan data, we demonstrated simultaneous IRAK4 inhibition and verified superior in vivo efficacy compared to gilteritinib using the FLT3-ITD MOLM-13 cell line derived xenograft (CDX) murine model (Elgamal OA et al., ASH 2022). Recognizing the exceptional safety profile of E2082-0047 in pre-clinical IND enabling toxicology studies, we moved forward to test the potency of E2082-0047 versus gilteritinib in cells harboring the FLT3-ITD-F691L gatekeeper mutation using two in vivo models, MOLM-14-F691L CDX model and a novel immunocompetent murine adoptive transfer model that does not require conditioning or irradiation. This model is generated by the crossing of the CD45.2 specific Npm1 cA cre inducible model (Vassiliou et al., 2011) with the Flt3 ITD (Lee et al., 2007) model which was previously reported to harbor a F692L mutation, analogous to the human F691L mutation (Dovey et al., 2016) thus, generating the Npm1 cA;Flt3 ITD-F692L AML murine model.In the MOLM-14-F691L CDX model study, we found a consistent reduction in human CD45 cells in bone marrow and increased survival benefit in mice receiving E2082-0047 compared to gilteritinib. Further, mice in the gilteritinib group with progressing disease (> 50% human CD45+ cells in bone marrow) were switched to E2082-0047 with consequent > 5-fold reduction in bone marrow tumor burden within 8 days. These data suggest that E2082-0047 will be effective in gilteritinib resistant disease. Strikingly, in the AML adoptive transfer model, E2082-0047 resulted in a compelling long-term survival benefit. In our first study (donor #1), vehicle and gilteritinib cohorts had 29- and 32-days median survival, respectively with evident circulating CD45.2 AML. In the E2082-0047 cohort, mice remained on study with an average of <2% circulating CD45.2 cells therefore, we stopped treatment and euthanized three mice for tissue collection, leaving eight mice for disease relapse monitoring for an additional two weeks where we lost 3/8 mice due to early removal criteria (ERC) and 5/8 were euthanized at end of study day 100, with an average of <10% circulating CD45.2 cells. This initial study showed the capacity for E2082-0047 to induce long-term survival in a model with a clinically relevant TKD gatekeeper mutation. We repeated our study with a more aggressive donor (donor #2) where vehicle and gilteritinib arms had a median survival of 22 days. While mice receiving E2082-0047 remain on study (week 8 of an ongoing study), with an average of <5% peripheral blood CD45.2 level (Figure 1).Collectively, our previous and follow-up studies herein demonstrate the superiority of E2082-0047 over gilteritinib against FLT3-ITD and with TKD mutations including the gatekeeper F691L variant. We demonstrate significantly improved survival after E2082-0047 treatment in an immune deficient in vivo model of FLT3-ITD/TKD-F691L MOLM-14 AML and a durable long-term survival in a large subset of mice using two donors in an immune competent adoptive transfer model of NPM1+FLT3-ITD/TKD-F692L AML. Given the curative potential of E2082-0047 in the immune competent model, ongoing efforts are focused on investigating the host immune response to AML. Given the safety and efficacy studies performed with E2082-0047 to date, a healthy volunteer study to best estimate dose for trials in AML is ongoing.

2022-11-15·Blood

A Novel Inhibitor of FLT3 and Its Drug-Resistant Mutants with Superior Activity to Gilteritinib in Molm-13 Preclinical Acute Myeloid Leukemia Xenograft Model

作者: Abagyan, Ruben ; Savchuk, Nikolay ; Byrd, John C. ; Elgamal, Ola A ; Riakhovskii, Alexei ; Karapetian, Ruben ; Baker, Sharyn ; Dukes, Iain ; Stearns, Blaise ; Bulanova, Elena ; Mitkin, Oleg ; Mullaney, Allison ; Kysil, Volodymyr ; Stahl, Emily ; Ivachtchenko, Alexandre ; Hertlein, Erin ; Orry, Andrew ; Lerma, James R ; Parchinsky, Vladislav ; Gukasyan, Hovhannes ; Pushechnikov, Alexei ; Lam, Polo Chun-Hung

项与 ChemDiv, Inc. 相关的新闻（医药）

2024-05-13

·PRNewswire

ChemDiv to Participate in the EF Hutton Annual Global Conference, May 15, 2024

SAN DIEGO, May 13, 2024 /PRNewswire/ -- ChemDiv, Inc, announced today that Bill Farley, CEO, will participate in the EF Hutton Annual Global Conference (). The conference is being held in person at The Plaza Hotel, NY, NY 10019 on May 15, 2024. Bill Farley, CEO of ChemDiv, will provide corporate updates and highlights associated with ChemDiv's growth and development through partnerships with multiple venture backed accelerators, leveraging AI/LLM, chemical libraries, integrated biology and development with over 26 assets in the pipeline. These assets cover a broad range of therapeutic areas such as oncology, inflammation, CVMD, and anti-infectives. About ChemDiv Inc ChemDiv is a globally recognized leader in drug discovery solutions, offering fully integrated R&D services to support pharmaceutical projects. With over three decades of experience, ChemDiv delivers leads, drug candidates, and new drugs across various therapeutic areas to partners worldwide. For more information about ChemDiv visit . For media inquiries, please contact: Bill Farley CEO of ChemDiv [email protected] SOURCE ChemDiv

2024-01-03

·PRNewswire

ChemDiv Marks a Milestone as Orionis Biosciences' Novel Immunotherapy Enters Phase I Clinical Trials

SAN DIEGO, Jan. 3, 2024 /PRNewswire/ -- ChemDiv Inc, a leading provider of drug discovery platforms and development solutions, celebrates a significant milestone in collaboration with Orionis Biosciences: the commencement of Phase I clinical trials for ORB-011, a cutting-edge attenuated, cis-targeted interferon immunotherapy compound. ORB-011, a pioneering clinical candidate emerging from Orionis' innovative A-Kine® platform, is the culmination of rigorous research and development efforts facilitated by ChemDiv's robust covalent and bifunctional chem-bio arsenal. Engineered to exhibit highly selective, targeted activation of tumor-antigen-presenting cDC1 dendritic cells, ORB-011 leverages ChemDiv's expertise in warheads to optimize interferon's therapeutic potential while mitigating broad systemic activity and associated toxicities characteristic of traditional cytokine therapies. "We take immense pride in our support of Orionis Biosciences' discovery and development, which has culminated in the advancement of ORB-011 into clinical trials," said ChemDiv's CEO, Bill Farley. "This marks a significant step in harnessing intrinsic immunobiology pharmacologically, and we are excited about the potential impact it may have on revolutionizing cancer therapeutics." The initiation of Phase I clinical trials for ORB-011 is a significant milestone, underscoring the transformative potential of ChemDiv and Orionis Biosciences synergistic research, pushing the boundaries of collaborative drug discovery to improve patient outcomes in the fight against cancer. About ChemDiv Inc: ChemDiv is a globally recognized leader in drug discovery solutions, offering fully integrated R&D services to support pharmaceutical projects. With over three decades of experience, ChemDiv delivers leads, drug candidates, and new drugs across various therapeutic areas to partners worldwide. For more information about ChemDiv visit . For media inquiries, please contact: Bill Farley CEO of ChemDiv [email protected] SOURCE ChemDiv

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2023-12-28

·PRNewswire

ChemDiv Forges Strategic Partnership with The University of Texas Medical Branch (UTMB) to Expand Its High-throughput Screening Research Capabilities

SAN DIEGO, Dec. 28, 2023 /PRNewswire/ -- ChemDiv, a global leader in drug discovery solutions, announces a strategic collaboration with the University of Texas Medical Branch (UTMB) to facilitate the expansion of its inventory and advance the institution's High-throughput Screening (HTS) research programs. ChemDiv's comprehensive suite of fully integrated Research & Development services offers UTMB unparalleled support in its pursuit of groundbreaking medical research. By leveraging ChemDiv's 32 years of experience, advanced capabilities, and a seasoned team of experts, UTMB aims to push the boundaries of medical research and translate discoveries into tangible treatments for pressing medical needs. "At ChemDiv, we are dedicated to catalyzing pioneering research, and our collaboration with UTMB exemplifies our commitment to advancing healthcare globally," said Bill Farley, CEO of ChemDiv. "Our team's expertise and cutting-edge resources are poised to significantly augment UTMB's HTS research center, accelerating the discovery of novel therapeutic solutions." About ChemDiv: ChemDiv is dedicated to partnering in discovery and development of breakthrough therapies based on its unique chem-bio platforms: molecular glues, stabilizers and degraders; covalent and non-covalent binders; bifunctional molecules for synergistic effect and synthetic lethality. Over the past 32 years ChemDiv has successfully completed hundreds of lead, candidate and new drug programs to treat cancer, neurological, infectious, cardiometabolic and immune diseases with pharma, biotech and academic partners around the globe. For more information about ChemDiv, visit . For further information, please contact: Bill Farley CEO of ChemDiv Bfarley@chemdiv.com SOURCE ChemDiv

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药物(靶点)	适应症	全球最高研发状态

AVN-322 ( 5-HT6 receptor )	阿尔茨海默症更多	临床2期
BCL2 inhibitor(ChemDiv) ( Bcl-2 )	B细胞恶性肿瘤更多	临床前
E2082-0047 ( FLT3 )	急性髓性白血病更多	临床前
2082-0047 ( FLT3 )	成人急性髓性白血病更多	临床前
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