G1 Therapeutics, Inc.

Gi Therapeutics, Inc.

Pharmacosmos Holding A/s

Harvard College

The Brigham and Women's Hospital, Inc.

The University of North Carolina at Chapel Hill

University of Illinois

Pharmacosmos A/s

Jay Copeland Strum

Francis Xavier Tavares

Patrick Joseph Roberts

John Emerson Bisi

Jessica A Sorrentino

Hannah S White

Alexander Smith

Stephen E Schneider

Jaroslaw Mazurek

Robert C Gadwood

Andrew Beelen

Ricky D Gaston

Gregory R Thatcher

Kwok-kin Wong

David Kendall Jung

Rui Xiong

Jiong Zhao

Debra A Tonetti

Norman E Sharpless

Benjamin D Humphreys

Anne Y Lai

Derek P DiRocco

An advantageous isolated morphic form of trilaciclib which is 2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one, for example in the form of a dihydrochloride salt or a dihydrochloride, dihydrate.

Morphic forms of trilaciclib and methods of manufacture thereof

A G1T38 human oral dosage regime that provides a (mean AUC(0-24),ss (h*ng/mL))/(dose (mg)) ratio of less than 5 and/or a (mean AUC(0-24),ss (h*ng/mL))/(Absolute Neutrophil Count (cells/mm3)) ratio on day 22 of dosing of not greater than 1.25.

G1T38 superior dosage regimes

This invention is in the area of cell cycle inhibiting compounds for the treatment of disorders involving abnormal cellular proliferation, and include selective CDK2 inhibitors for medical therapy and their pharmaceutically acceptable salts and compositions. The inhibitors are pyrimidine-based N-heterocyclic compounds of formula:

Substituted 1',2′-dihydro-3′H-spiro[cyclohexane-1,4′-pyrimido[5′,4′:4,5]pyrrolo[2,1-c][1,2,4]triazin]-3′-ones as cyclin-dependent kinase inhibitors

This invention is in the area of improved therapeutic combinations for and methods of treating selected retinoblastoma (Rb)-negative cancers and Rb-negative abnormal cellular proliferative disorders using particular topoisomerase inhibitors and specific cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. In one aspect, the improved treatment of select Rb-negative cancers is disclosed using specific compounds disclosed herein in combination with a topoisomerase I inhibitor.

Treatment of Rb-negative tumors using topoisomerase inhibitors in combination with cyclin dependent kinase 4/6 inhibitors

An advantageous isolated morphic form of trilaciclib which is 2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one, for example in the form of a di-hydrochloride salt or a dihydrochloride, dihydrate.

This invention is in the area of improved compounds, compositions and methods of transiently protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC) as well as renal cells, from damage associated with DNA damaging chemotherapeutic agents. In one aspect, improved protection of healthy cells is disclosed using disclosed compounds that act as highly selective and short, transiently-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects undergoing DNA damaging chemotherapeutic regimens for the treatment of proliferative disorders.

Transient protection of normal cells during chemotherapy

This invention is in the area of improved compounds for and methods of treating selected RB-positive cancers and other Rb-positive abnormal cellular proliferative disorders while minimizing the deleterious effects on healthy cells, for example healthy Hematopoietic Stem Cells and Progenitor Cells (HSPCs), associated with current treatment modalities. In one aspect, improved treatment of select RB-positive cancers is disclosed using specific compounds disclosed herein. In certain embodiments, the compounds described herein act as highly selective and, in certain embodiments, short, transiently-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects.

HSPC-sparing treatments for RB-positive abnormal cellular proliferation

This invention is in the area of cell cycle inhibiting compounds for the treatment of disorders involving abnormal cellular proliferation, and include selective CDK2 inhibitors for medical therapy and their pharmaceutically acceptable salts and compositions. The inhibitors are pyrimidine-based N-heterocyclic compounds of formula: 

Substituted 1',2&#x2032;-dihydro-3&#x2032;H-spiro[cyclohexane-1,4&#x2032;-pyrimido[5&#x2032;,4&#x2032;:4,5]pyrrolo[2,1-c][1,2,4]triazin]-3&#x2032;-ones as cyclin-dependent kinase inhibitors

The addition of a selective, fast-acting, short half-life CDK 4/6 inhibitor in a very specific dosage regimen to the combination of chemotherapy with a checkpoint inhibitor provides superior results in the treatment of a tumor or cancer. The unexpected discovery is that the short pulsatile specifically-timed administration of a selective, fast-acting, short half-life CDK 4/6 inhibitor during administration of the chemotherapy portion of the triple combination therapy has a profound effect on the immune cells in the cancer microenvironment.

Preservation of immune response during chemotherapy regimens

This invention directed to methods for treating select RB-positive cancers and other Rb-positive abnormal cellular proliferative disorders using CDK4/6 inhibitors in specific dosing and combination or alternation regimes. In one aspect, treatments of select RB-positive cancers are disclosed using specific CDK4/6 inhibitors in combination or alternation with a Bruton's tyrosine kinase (BTK) inhibitor.

Anti-neoplastic combinations and dosing regimens using CDK4/6 inhibitor compounds to treat Rb-positive tumors

The present invention provides methods for treating a EGFR-mutant cancer in a patient by administering a selective CDK4/6 inhibitor described herein in combination or alternation with an EGFR-TKI to delay or reverse acquired resistance to previously administered EGFR-TKIs. In addition, methods for treating a EGFR-mutant cancer in a patient by administering a selective CDK4/6 inhibitor described herein in combination or alternation with an EGFR-TKI are provided wherein an intrinsically EGFR-TKI resistant EGFR-mutant cancer is sensitized to the effects of the EGFR-TKI.

Treatment of EGFR-driven cancer with fewer side effects

Compositions, combinations and methods comprising a CDK4/6 inhibitor of Formula D with a selective estrogen receptor downregulator of Formula A, B or C that are advantageous for the treatment of abnormal cellular proliferation, including a cancer or a tumor.

Growing community of inventors

Hillsborough, NC, United States of America

Jay Copeland Strum