overview mechanism of action pfizer investigational agents...

Rationale for a Cancer Target

Mechanism of Action

AxitinibRTKI includingVEGFR-1,2,3

Overview

Stage of Development

NPU00667_25cNOVEMBER 2017

Pfizer Investigational Agents for

Breast Cancer Now (BCN) Catalyst

Program


Mechanism of Action


Overview



AxitinibRTKI including VEGFR-1,2,3

NOVEMBER 2017


Mechanism of Action


Overview



Overview

Overview

INLYTA® (axitinib) (package insert). New York, New York: Pfizer Inc. September 2013.

Kania RS (Pfizer San Diego). Structure-based design and characterization of axitinib. In Li R, Stafford JA, eds.

Kinase Inhibitor Drugs (Wiley Series in Drug Discovery and Development). Hoboken, NJ: John Wiley & Sons,

Inc.; 2009: chapter 7: doi:10.1002/9780470524961.ch7.

• The vascular endothelial growth factor (VEGF)

family of proangiogenic proteins are key regulators

of many of the signaling networks contributing to

angiogenesis

• The VEGF receptors are implicated in pathologic

angiogenesis, tumor growth, and cancer

progression

• Axitinib is a small molecule substituted indazole

derivative that inhibits receptor tyrosine kinases,

including VEGFR-1, VEGFR-2, and VEGFR-3, at

therapeutic plasma concentrations

• VEGF-mediated endothelial cell proliferation and

survival were inhibited by axitinib in vitro and in

mouse models

• Axitinib was shown to inhibit tumor growth and

phosphorylation of VEGFR-2 in tumor xenograft

mouse models


Mechanism of Action


Overview




Sponsored by SFJ Pharmaceuticals, Inc. Closed to enrollment

ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed November 8, 2017

Axitinib is being investigated as a single agent or

in combination with other agent(s) in the following

tumor types. Axitinib is not approved for the uses

listed below.


Adjuvant

Renal Cell

Carcinoma

(RCC)

Phase 3 *

Advanced Renal

Cell Carcinoma

(RCC)

Phase 3: Combination


Mechanism of Action

BosutinibABL and Src Kinase Inhibitor

Overview


NPU00667_25c NOVEMBER 2017


NOVEMBER 2017


Mechanism of Action


Overview



Overview

• The Philadelphia chromosome is a reciprocal translocation

that fuses the Abl locus on chromosome 9 with the Bcr locus

on chromosome 22, resulting in overexpression of the

constitutively active protein tyrosine kinase Bcr-Abl, which is

commonly associated with chronic myeloid leukemia (CML)

• The Src family of tyrosine kinases plays a role in a variety of

normal cellular functions including proliferation, differentiation,

survival etc. and are frequently overexpressed and/or

aberrantly activated in many tumors

• Bosutinib is a synthetic quinolone derivative and kinase

inhibitor that targets both Abl and Src kinases with potential

antineoplastic activity

• Bosutinib inhibits Bcr-Abl in several CML cell lines and

transfectants, with IC50 values in the low nanomolar range and

also inhibited Bcr-Abl kinase activity in CML CD34+ cells

• Bosutinib inhibits Src in an enzyme assay with an IC50 of 1.2

nM, inhibits anchorage-independent growth of Src-transformed

fibroblasts with an IC50 of 100 nM, and inhibits Src-dependent

protein tyrosine phosphorylation

Overview

Bumbea H., et al: Journal of Medicine and Life: Volume 3, Number 2, April-June 2010.

Golas JM, Arndt K, Etienne C, et al. Cancer Res. 2003;63(2):375-381.

Konig H, Holyoake TL, Bhatia R. Blood. 2008;111(4):2329-2338.

Puttini M, Coluccia AM, Boschelli F, et al. Cancer Res. 2006;66(23):11314-11322.

Vultur A, Buettner R, Kowolik C, et al. Mol Cancer Ther. 2008;7(5):1185-1194.


Mechanism of Action


Overview




ClinicalTrials.gov. http://clinicaltrials.gov. Accessed November 7, 2017.

Bosutinib is being investigated in the following

tumor type. Bosutinib is not approved for the use

listed below.


Newly

Diagnosed

Chronic Phase (CP)

Chronic Myeloid

Leukemia (CML)

Phase 3*

* Closed to enrollment


Mechanism of Action

GedatolisibPI3K/mTOR Pathway Inhibitor

Gedatolisib is an investigational compound

Overview




NOVEMBER 2017



Mechanism of Action



Overview



Overview

• Phosphatidylinositol 3-kinases (PI3Ks) activate a signaling

pathway which includes the protein kinases AKT and

mTOR, leading to regulation of cell growth, cell cycle

progression, apoptosis, migration, metabolism, and

vesicular trafficking

• The PI3K/AKT/ mTOR pathway is one of the most

frequently mutated pathways in solid tumor malignancies,

resulting in activation of PI3K and its downstream targets

AKT and mTOR

• PF-05212384 is a small molecule inhibitor of the

PI3K/AKT/mTOR signaling pathway

• In vitro, PF-05212384 has demonstrated suppression of

PI3K (and mTOR) kinase activity in a diverse array of

tumor cell lines, and in vivo the compound has inhibited

tumor cell growth and induced tumor regression in human

tumor xenograft models with select gene mutations

• PF-05212384 shows antitumor activity in subcutaneous

and orthotopic human xenograft tumor models when

administered intravenously (iv) as a single agent

Overview

Arcaro A, Guerreiro AS. Curr Genomics. 2007;8(5):271-306.

Grant S. J Clin Invest. 2008;118(9):3003-3006.

Mallon RG, Feldberg LR, Lucas J, et al. Clin Cancer Res. Feb 15, 2011.

Data on file, Wyeth May 2009


Mechanism of Action



Overview



Mechanism of Action

Mechanism of Action

Adapted from Workman P, et al. Nat Biotech. 2006;24:794-796. Used with permission from AACR.

Cheng H, et al. Med. Chem. Commun. 2010;1:139-144.

Mallon RG, et al. Clin Cancer Res. Feb 15, 2011.


Mechanism of Action



Overview






Metastatic HR+

Breast Cancer

(MBC)

Phase 1 Combination

Metastatic

Triple Negative

Breast Cancer

(TNBC)

Phase 1 Combination


Mechanism of Action

GlasdegibSmoothened (SMO) Inhibitor

Glasdegib is an investigational compound

Overview




NOVEMBER 2017



Mechanism of Action



Overview



Overview

• The Hedgehog (Hh) signal transduction pathway is essential

for the patterning and development of tissues in metazoan

organisms

• The hedgehog receptor, patched homologue 1 (PTCH1),

inhibits smoothened (SMO), a key activator in the pathway

• During physiologic signaling, Hh binds to PTCH1 on neighboring

cells, thereby allowing SMO to activate hedgehog signaling.

• SMO activation results in activation of target proteins, such as GLI

transcription factors, which can cause proliferation, survival, and

differentiation of cells.

• PF-04449913 is an orally bioavailable small-molecule inhibitor

of the Hedgehog (Hh) signaling pathway with potential

antineoplastic activity

• In vivo, PF-04449913 was shown to revert multidrug

resistance (MDR) by down-regulation of ABCA2 and BCL2 on

leukemia stem cells in acute myeloid leukemia and chronic

myeloid leukemia

• PF-04449913-treated medulloblastoma allografts had reduced

levels of GLI1 gene expression and downregulation of genes

linked to the Hh signaling pathway

Overview

NCI Drug Dictionary. Accessed April 14, 2011..

Jackson-Fisher A, McMahon MJ, Lam J, et al. AACR 2011. Abstract 4504.

Papayannidis, C., Cancer Research: April 15, 2012; Volume 72, Issue 8, Supplement 1


Mechanism of Action



Overview



Mechanism of Action

• The Hedgehog pathway is expressed in all 3 germ layers

throughout embryogenesis

• The Hedgehog pathway is repressed in adult tissues but, if

aberrantly reactivated, can induce neoplasia

• Soluble Hh binds PTCH1 to release SMO and activate GLI

signaling

• Inappropriate SMO signaling is implicated in multiple human

malignancies

• The Hedgehog pathway regulates cancer stem cell maintenance

and activity

Mechanism of Action

Zhao C, Chen A , Jamieson CH, et. al. Nature. 2009;(458):776-779..

Ingham PW, et al. Genes Dev. 2001;15:3059-3087.

Xie J. Acta Biochim Biophys Sin (Shanghai). 2008;40(7):670-680.


Mechanism of Action



Overview






Acute Myeloid

Leukemia (AML)

or Myelodysplastic

Syndrome (MDS)

Phase 2 *

Myelofibrosis Phase 2


Myelodysplastic

Syndrome (MDS)

Acute Myeloid

Leukemia (AML) or

Chronic Myelomonocytic

Leukemia (CMML)

Phase 1b/2 Combination

LorlatinibALK/ROS1 Inhibitor

Lorlatinib is an investigational compound


Mechanism of Action


Overview



NOVEMBER 2017





Mechanism of Action


Overview


Overview

• A variety of human malignancies have anaplastic lymphoma kinase

(ALK) translocations, amplifications, or oncogenic mutations,

including non-small cell lung cancer (NSCLC), anaplastic large

cell lymphoma, inflammatory myofibroblastic tumors, and

neuroblastoma

• ROS1 is a receptor tyrosine kinase (RTK) implicated in tumor

progression, and the first oncogenic fusion of ROS1 (FIG-ROS1)

was discovered in glioblastoma

• Elevated ROS expression has also been observed in

cholangiocarcinoma, NSCLC, and breast cancer

• PF-06463922 is an ATP-competitive small molecule inhibitor of

both ALK and ROS1, created through structure-based drug design

(SBDD), with specific considerations such as a low efflux in cell

lines overexpressing P-glycoprotein and breast cancer resistance

protein, providing blood-brain barrier and cell penetration properties

• PF-06463922 shows antitumor activity in preclinical models which

harbor the resistant mutations ALK-G1202R and ROS1-G2032R

• Single-dose preclinical rat in vivo studies of PF-06463922 showed

oral bioavailability and CNS availability, with brain levels

approximately 30% of that in the plasma

Overview

Johnson TW, Bailey S, Burke BJ, et al. EORTC 2013 Poster 982: Is CNS availability a no-brainer? La Jolla,

CA: Pfizer Oncology.

Mossé YP, Wood A, Maris JM. Inhibition of ALK Signaling for Cancer Therapy. Clin Cancer Res.

2009;15(18):5609-5614.

Gu T, Deng X, Huang F, et al. PLoS ONE. 2010;6(1): e15640.

Rimkunas, VM, Clin Cancer Res; 18(16) August 15, 2012




Mechanism of Action


Overview

Stage of DevelopmentStage of Development




ALK+

Non-Small Cell

Lung Cancer

(NSCLC)

Phase 3

ALK+ /ROS1+

Non-Small Cell

Lung Cancer

(NSCLC)

Phase 2 *


Mechanism of Action

PalbociclibCDK 4/6 Inhibitor

Overview

Stage of Development Page 1

Page 2



NOVEMBER 2017


Mechanism of Action


Overview


Page 2


Overview

Overview

Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.

Fry DW, et al. Mol Cancer Ther. 2004;3(11):1427-1438.

Knudsen ES, Wang JY. Clin Cancer Res. 2010;16(4):1094-1099.

• Cyclin-dependent kinases (CDKs) are small serine/threonine

kinases that play a key role in regulating cell cycle progression

and to a large degree govern cellular transitions from growth

phases (G1 and G2) into phases associated with DNA

replication (S) and mitosis (M)

• Progression through the G1-S phase requires phosphorylation

of the retinoblastoma (Rb) protein by CDK4 or CDK6 in

complex with their activating subunits, the D-type cyclins

• Components of this pathway, particularly cyclin D1 and Rb, are

frequently altered in sporadic human cancers to promote

deregulated cellular proliferation

• Palbociclib is an orally active inhibitor of CDK4 and CDK6

kinases. Inhibition results in decreased phosphorylation of the

CDK4/6 target retinoblastoma protein

• Blocking Rb phosphorylation prevents cell cycle progression in

sensitive cell lines

• Palbociclib has been shown, in vitro, to induce growth arrest in

the G1 phase of the cell cycle in multiple Rb+ tumor cell line

models. Palbociclib causes a specific cell cycle arrest in G1

phase and inhibits proliferation in cultured and xenografted

leukemia, myeloma, breast cancer, colon cancer, and lung

cancer cells.


Mechanism of Action


Overview


Page 2



Palbociclib is being investigated as a single agent or in

combination with other agent(s) in the following tumor types.

Palbociclib is not approved for the uses listed below.


HR+/HER2-

Adjuvant Breast

Cancer

Phase 3: Combination*

Phase 3: Combination** HR+/HER2 normal

Adjuvant Breast

Cancer

HR+/HER2-

Metastatic

Breast Cancer

Phase 3: Combination†

HR+/HER2+

Metastatic

Breast Cancer

Phase 3: Combination◊

* Sponsored by Alliance Foundation Trials, LLC.

For Stage II or III breast cancer patients

** Sponsored by German Breast Group.

For high risk breast cancer patients. No longer

screening

† Sponsored by Spanish Breast Cancer Group ◊ Sponsored by Alliance Foundation Trials, LLC.

ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed. November 8, 2017


Mechanism of Action


Overview


Page 2



Page 2

ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed. November 8, 2017

Palbociclib is being investigated as a single agent or in

combination with other agent(s) in the following tumor

types. Palbociclib is not approved for the uses listed

below.


Recurrent/

Metastatic

Squamous Cell

Carcinoma of the

Head & Neck (SCCHN)



Metastatic

Pancreatic Ductal

Adenocarcinoma

(PDAC)

Relapsed/

Refractory

Mantle Cell

Lymphoma

Phase 1: Combination*

* Sponsored by National Cancer Institute (NCI). Closed to enrollment


Mechanism of Action

SunitinibMultiple RTK Inhibitor

Overview




NOVEMBER 2017


Mechanism of Action


Overview



Overview

Overview

Pytel D, Sliwinski T, Poplawski T, et al. Anticancer Agents Med Chem. 2009;9(1):66-76.

SUTENT® (sunitinib malate) (package insert). New York, New York: Pfizer Inc. August 2013.

• Tyrosine kinases are enzymes which phosphorylate

tyrosine residue on targeted proteins. They stimulate

cellular pathways involved in such functions as growth,

proliferation, migration, synthesis, and apoptosis

• Sunitinib is an orally administered small molecule that

inhibits multiple receptor tyrosine kinases (RTKs), some

of which are implicated in tumor growth, pathologic

angiogenesis, and metastatic progression of cancer

• Sunitinib was identified as an inhibitor of platelet-derived

growth factor receptors (PDGFRα and PDGFRβ), vascular

endothelial growth factor receptors (VEGFR1, VEGFR2,

and VEGFR3), stem cell factor receptor (KIT), Fms-like

tyrosine kinase-3 (FLT3), colony-stimulating factor

receptor Type 1 (CSF-1R), and the glial cell-line derived

neurotrophic factor receptor (RET)

• Sunitinib inhibition of the activity of these RTKs has been

demonstrated in biochemical and cellular assays, and

inhibition of function has been demonstrated in cell

proliferation assays


Mechanism of Action


Overview






Sunitinib is being investigated as a single agent in

the following tumor type. Sunitinib is not approved

for the use listed below.


Pediatric

Advanced

Gastrointestinal

Stromal Tumor

(GIST)

Phase 2 *


Mechanism of Action

TalazoparibPARP Inhibitor

Talazoparib is an investigational compound

Overview




NOVEMBER 2017



Mechanism of Action



Overview



Overview

Overview

Underhill et al. Ann Oncol. 2011;22(2):268‐279

NCI Drug Dictionary. https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=694964.

Accessed 10.23.16

Murai et al. Mol Cancer Ther. 2014;13:433-443.

https://newdrugapprovals.org/2016/02/08/talazoparib/. Accessed 10.23.16

Wainberg et al. AACR 2016 Abstract CT011.

Medivation Brochure CTSITE-MULTI-TALA-0001 03/16

• Poly (ADP-ribose) polymerase (PARP) enzymes are

associated with DNA repair, specifically base excision repair, a

key pathway in the repair of DNA single-strand breaks (SSB).

They are thought to play a role in repair of damaged DNA and

in stabilization of the genome

• Talazoparib is a dual inhibitor of the nuclear enzyme PARP

with potential antineoplastic activity

• Talazoparib is designed to inhibit PARP and trap PARP on DNA,

with the goal of preventing PARP-mediated DNA damage repair

thereby inducing tumor cell death in BRCA1/2-mutated tumor cells

• Talazoparib selectively binds to PARP and is thought to

prevent PARP mediated DNA repair of single strand DNA

breaks via the base-excision repair pathway

• This enhances the accumulation of DNA strand breaks, promotes

genomic instability and eventually leads to apoptosis. PARP

catalyzes post-translational ADP-ribosylation of nuclear proteins

that signal and recruit other proteins to repair damaged DNA and is

activated by single-strand DNA breaks


Mechanism of Action



Overview



Mechanism of Action

Mechanism of Action

Figure adapted from Cancer Res. 2012. 72:5588-5599. Murai J et al. Trapping of PARP1 and

PARP2 by Clinical PARP Inhibitors, with permission from AACR.

Possible dual cytotoxic mechanisms of PARP inhibitors:

1: Catalytic inhibition (upper pathway) is thought to

interfere with the repair of SSBs, leading to replication fork

damage that requires homologous recombination (HR)

repair

2: Trapping of PARP-DNA complexes may also lead to

replication fork damage but utilizes additional repair

pathways including Fanconi pathway (FA), template

switching (TS), ATM, FEN1 (replicative flap endonuclease)

and polymerase β.


Mechanism of Action



Overview






Locally Advanced

or Metastatic

Breast Cancer with

Germline

BRCA mutations

Phase 3 *

Metastatic

Castration-Resistant

Prostate Cancer

(MCRPC)

Phase 3

Locally Advanced

or Metastatic

Solid TumorsPhase 1b Combination


overview mechanism of action pfizer investigational agents...

Documents