CALR modulators(calreticulin modulators), CD38 inhibitors(Lymphocyte differentiation antigen CD38 inhibitors), CD47 inhibitors(Cluster of differentiation 47 inhibitors)

+ [1]

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Adult Acute Myeloblastic Leukemia

Inactive Indication-

Originator Organization

The Ohio State University

University of Cincinnati Physicians Co. LLC

Active Organization

The Ohio State University

University of Cincinnati Physicians Co. LLC

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with Hosu-53

100 Translational Medicine associated with Hosu-53

100 Patents (Medical) associated with Hosu-53

Literatures (Medical) associated with Hosu-53

22 Apr 2024·JCI Insight

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia

Article

Author: Orwick, Shelley J ; Stillwell, Cody ; Elgamal, Ola A ; Vibhute, Sandip ; Abdulrahim, Mouad ; Xie, Zhiliang ; Byrd, John C ; Pan, Jianmin ; Patrick, Jeffrey ; Curran, Emily ; Rai, Jayesh ; Rai, Shesh N ; Goodwin, Thomas E ; Hertlein, Erin ; Phelps, Mitch A ; Mehmood, Abeera ; Carmichael, Bridget ; Tridandapani, Susheela ; Wunderlich, Mark ; Fobare, Sydney ; Stearns, Blaise ; Truxall, Jean ; Coss, Christopher C ; Mims, Alice S ; Hilinski, Gerard ; Baker, Sharyn D ; Vroom, Dennis C ; Bennett, Chad E ; Santhanam, Ramasamy ; Johnson, Mariah L ; Stahl, Emily ; Ezzell, Janel K ; Lerma, James R

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.

100 Deals associated with Hosu-53

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Adult Acute Myeloblastic Leukemia	Preclinical	US	University of Cincinnati Physicians Co. LLC	12 Dec 2022
Adult Acute Myeloblastic Leukemia	Preclinical	US	The Ohio State University	12 Dec 2022

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